Substituted Indoles and Their Use as Integrin Antagonists

ABSTRACT

The present invention relates to novel substituted indole compounds that are antagonists of alpha V (αv) integrins, for example α v β 3  and α v β 5  integrins, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The compounds may be used in the treatment of pathological conditions mediated by α v β 3  and α v β 5  integrins, including such conditions as tumor growth, metastasis, restenosis, osteoporosis, inflammation, macular degeneration, diabetic retinopathy, and rheumatoid arthritis. The compounds have the general formula:  
                 
 
where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , D, X, W, a, m, n, i, j, k and v are defined herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel substituted indole compounds thatare antagonists of alpha V (αv) integrins, for example α_(v)β₃ andα_(v)β₅ integrins, their pharmaceutically acceptable salts, andpharmaceutical compositions thereof.

2. Related Art

Integrins are cell surface glycoprotein receptors which bindextracellular matrix proteins and mediate cell-cell andcell-extracellular matrix interactions (generally referred to as celladhesion events) (Hynes, R. O., Cell 69:11-25 (1992)). These receptorsare composed of noncovalently associated alpha (α) and beta (β) chainswhich combine to give a variety of heterodimeric proteins with distinctcellular and adhesive specificities (Albeda, S. M., Lab. Invest. 68:4-14(1993)). Recent studies have implicated integrins in the regulation ofcellular adhesion, migration, invasion, proliferation, apoptosis andgene expression (Albeda, S. M., Lab. Invest. 68:4-14 (1993); Juliano,R., Cancer Met. Rev. 13:25-30 (1994); Ruoslahti, E. and Reed, J. C.,Cell 77:477-478 (1994); and Ruoslahti, E. and Giancotti, F. G., CancerCells 1:119-126 (1989)).

One member of the integrin family which has been shown to play asignificant role in a number of pathological conditions is the integrinα_(v)β₃, or vitronectin receptor (Brooks, P. C., DN&P 10(8):456-461(1997)). This integrin binds a variety of extracellular matrixcomponents and other ligands, including fibrin, fibrinogen, fibronectin,vitronectin, laminin, thrombospondin, and proteolyzed or denaturedcollagen (Cheresh, D. A., Cancer Met. Rev. 10:3-10 (1991) and Shattil,S. J., Thromb. Haemost. 74:149-155 (1995)). The two related αvintegrins, α_(v)β₅ and α_(v)β₁ (also vitronectin receptors), are morespecific and bind vitronectin (α_(v)β₅) or fibronectin and vitronectin(α_(v)β₁) (Horton, M., Int. J. Exp. Pathol. 71:741-759 (1990)). α_(v)β₃and the other integrins recognize and bind to their ligands through thetripeptide sequence Arg-Gly-Asp (“RGD”) (Cheresh, D. A., Cancer Met.Rev. 10:3-10 (1991) and Shattil, S. J., Thromb. Haemost. 74:149-155(1995)) found within all the ligands mentioned above.

The α_(v)β₃ integrin has been implicated in a number of pathologicalprocesses and conditions, including metastasis and tumor growth,pathological angiogenesis, and restenosis. For example, several studieshave clearly implicated α_(v)β₃ in the metastatic cascade (Cheresh, D.A., Cancer Met. Rev. 10:3-10 (1991); Nip, J. et al., J. Clin. Invest.95:2096-2103 (1995); and Yun, Z., et al., Cancer Res. 56:3101-3111(1996)). Vertically invasive lesions in melanomas are also commonlyassociated with high levels of α_(v)β₃, whereas horizontally growingnoninvasive lesions have little if any α_(v)β₃ (Albeda, S. M., et al.,Cancer Res. 50:6757-6764 (1990)). Moreover, Brooks et al. (in Cell79:1157-1164 (1994)) have demonstrated that systemic administration ofα_(v)β₃ antagonists disrupts ongoing angiogenesis on chickchorioallantoic membrane (“CAM”), leading to the rapid regression ofhistologically distinct human tumors transplanted onto the CAM. Theseresults indicate that antagonists of α_(v)β₃ may provide a therapeuticapproach for the treatment of neoplasia (solid tumor growth).

α_(v)β₃ has also been implicated in angiogenesis, which is thedevelopment of new vessels from preexisting vessels, a process thatplays a significant role in a variety of normal and pathologicalbiological events. It has been demonstrated that α_(v)β₃ is up-regulatedin actively proliferating blood vessels undergoing angiogenesis duringwound healing as well as in solid tumor growth. Also, antagonists ofα_(v)β₃ have been shown to significantly inhibit angiogenesis induced bycytokines and solid tumor fragments (Brooks, P. C., et al., Science264:569-571 (1994); Enenstein, J. and Kramer, R. H., J. Invest.Dermatol. 103:381-386 (1994); Gladson, C. L., J. Neuropathol. Exp.Neurol 55:1143-1149 (1996); Okada, Y., et al., Amer. J. Pathol.149:37-44 (1996); and Brooks, P. C., et al., J. Clin. Invest.96:1815-1822 (1995)). Such α_(v)β₃ antagonists would be useful fortreating conditions that are associated with pathological angiogenesis,such as rheumatoid arthritis, diabetic retinopathy, maculardegeneration, and psoriasis (Nicosia, R. F. and Madri, J. A., Amer. J.Pathol. 128:78-90 (1987); Boudreau, N. and Rabinovitch, M., Lab. Invest.64:187-99 (1991); and Brooks, P. C., Cancer Met. Rev. 15:187-194(1996)).

There is also evidence that α_(v)β₃ plays a role in neointimalhyperplasia after angioplasty and restenosis. For example, peptideantagonists and monoclonal antibodies directed to both α_(v)β₃ and theplatelet receptor α_(v)β₃ have been shown to inhibit neointimalhyperplasia in vivo (Choi, E. T., et al., J. Vasc. Surg. 19:125-134(1994); and Topol, E. J., et al., Lancet 343:881-886 (1994)), and recentclinical trials with a monoclonal antibody directed to both αII_(b)β₃and α_(v)β₃ have resulted in significant reduction in restenosis,providing clinical evidence of the therapeutic utility of β3 antagonists(Topol, E. J., et al., Lancet 343:881-886 (1994)).

It has also been reported that α_(v)β₃ is the major integrin onosteoclasts responsible for attachment to bone. Osteoclasts cause boneresorption. When bone resorbing activity exceeds bone forming activity,the result is osteoporosis, a condition which leads to an increasednumber of bone fractures, incapacitation and increased mortality.Antagonists of α_(v)β₃ have been shown to be potent antagonists ofosteoclastic activity both in vitro (Sato, M., et al., J. Cell Biol.111:1713-1723 (1990)) and in vivo (Fisher, J. E., et al., Endocrinology132:1411-1413 (1993)).

Lastly, White (in Current Biology 3(9):596-599 (1993)) has reported thatadenovirus uses α_(v)β₃ for entering host cells. The α_(v)β₃ integrinappears to be required for endocytosis of the virus particle and may berequired for penetration of the viral genome into the host cellcytoplasm. Thus compounds which inhibit α_(v)β₃ could be useful asantiviral agents.

The α_(v)β₅ integrin has been implicated in pathological processes aswell. Friedlander et al. have demonstrated that a monoclonal antibodyfor α_(v)β₅ can inhibit VEGF-induced angiogenesis in rabbit cornea andchick chorioallantoic membrane, indicating that the α_(v)β₅ integrinplays a role in mediating growth factor-induced angiogenesis(Friedlander, M. C., et al., Science 270:1500-1502 (1995)). Compoundsthat act as α_(v)β₅ antagonists could be used to inhibit pathologicalangiogenesis in tissues of the body, including ocular tissue undergoingneovascularization, inflamed tissue, solid tumors, metastases, ortissues undergoing restenosis.

Discovery of the involvement of α_(v)β₃ and α_(v)β₅ in such processesand pathological conditions has led to an interest in these integrins aspotential therapeutic targets, as suggested in the preceding paragraphs.A number of specific antagonists of α_(v)β₃ and α_(v)β₅ that can blockthe activity of these integrins have been developed. One major group ofsuch antagonists includes nonpeptide mimetics and organic-typecompounds. For example, a number of organic non-peptidic mimetics havebeen developed that appear to inhibit tumor cell adhesion to a number ofα_(v)β₃ ligands, including vitronectin, fibronectin, and fibrinogen(Greenspoon, N., et al., Biochemistry 32:1001-1008 (1993); Ku, T. W., etal., J. Amer. Chem. Soc. 115:8861-8862 (1993); Hershkoviz, R., et al.,Clin. Exp. Immunol. 95:270-276 (1994); and Hardan, L., et al., Int. J.Cancer 55:1023-1028 (1993)).

Additional organic compounds developed specifically as α_(v)β₃ orα_(v)β₅ integrin antagonists or as compounds useful in the treatment ofαv-mediated conditions have been described in several recentpublications.

For example, U.S. Pat. No. 5,741,796, issued Apr. 21, 1998, disclosespyridyl and naphthyridyl compounds for inhibiting osteoclast-mediatedbone resorption.

PCT Published Application WO 97/45137, published Oct. 9, 1997, disclosesnon-peptide sulfotyrosine derivatives, as well as cyclopeptides, fusionproteins, and monoclonal antibodies, that are useful as antagonists ofα_(v)β₃ integrin-mediated angiogenesis.

PCT Published Application WO 97/36859, published Oct. 9, 1997, disclosespara-substituted phenylpropanoic acid derivatives of the generalformula:

where A is:

B is —CH₂CONH—, —CONR⁵²—(CH₂)_(p)—, —C(O)O—, —SO₂NH—, —CH₂O—, or —OCH₂—;

Y¹ is selected from the group consisting of N—R², O and S;

Y³ and Z³ are independently selected from the group consisting of H,alkyl, aryl, cycloalkyl and aralkyl, or Y³ and Z³ taken together with Cform a carbonyl;

R⁵⁰ is selected from the group consisting of H, alkyl, aryl, carboxylderivative and —CONHCH₂CO₂R⁵³, wherein R⁵³ is H or lower alkyl; and

R⁵¹ is selected from the group consisting of H, alkyl, carboxylderivatives,

wherein R⁵⁴ is selected from the group consisting of H, alkyl,cycloalkyl, aryl, aralkyl, aralkenyl and aryl substituted by one or morealkyl or halo; and wherein R⁵⁵ is selected from the group consisting ofN-substituted pyrrolidinyl, piperidinyl and morpholinyl.

The publication also discloses the use of the compounds as α_(v)β₃integrin antagonists.

PCT Published Application WO 97/06791, published February 1997,discloses methods for inhibition of angiogenesis in tissue usingvitronectin α_(v)β₅ antagonists.

More recently, PCT Published Application WO 97/23451, published Jul. 3,1997, discloses tyrosine derivatives of the general formula:

wherein

X is C₁₋₆alkylene or 1,4-piperidyl;

Y is absent, O, CONH or —C^(˜)C—;

R¹ is H, CN, N₃, NH₂, H₂N—C(═NH), or H₂N—C(═NH)—NH, where the primaryamino groups can also be provided with conventional amino protectivegroups;

R² and R³ are independently H, A, A-SO₂—, Ar—SO₂—, camphor-10-SO₂—, COOAor a conventional amino protective group;

A and R⁴ are independently H, C₁₋₁₀alkyl, or benzyl; and

Ar is phenyl or benzyl, each of which is unsubstituted ormonosubstituted by CH₃;

and their physiologically acceptable salts.

The disclosed compounds are described as αv-integrin antagonists(especially α_(v)β₃ antagonists) useful in the treatment of tumors,osteoporoses, and osteolytic disorders and for suppressing angiogenesis.

PCT Published Application WO 98/00395, published Jan. 8, 1998, disclosesnovel tyrosine and phenylalanine derivatives as αv integrin andGPIIb/IIIa antagonists having the general formula:

wherein

X can be, among other groups, alkyl, aryl or cycloalkyl;

Y and Z can be alkyl, O, S NH, C(═O), CONH, NHCO, C(═S), SO₂NH, NHSO₂,CA=CA! or —C^(˜)C—;

R¹ can be H₂N—C(═NH) or H₂N—(C═NH)—NH;

R² is A, aryl or aralkyl;

R³ is hydrogen or A;

R⁴ is hydrogen, halogen, OA, NHA, NAA!, —NH-Acyl, —O-Acyl, CN, NO₂, SA,SOA, SO₂A, SO₂Ar or SO₃H; and

A and A! can be hydrogen, alkyl or cycloalkyl.

The publication discloses the use of the compounds in pharmaceuticalpreparations for the treatment of thrombosis, infarction, coronary heartdisease, tumors, arteriosclerosis, infection and inflammation.

SUMMARY OF THE INVENTION

The present invention is directed to substituted indoles having FormulaIV (below). Also provided is a process for preparing compounds ofFormula IV. The novel compounds of the present invention exhibitinhibition of α_(v)β₃ and α_(v)β₅ integrin receptor binding. Alsoprovided is a method of treating α_(v)β₃ integrin- and α_(v)β₅integrin-mediated pathological conditions such as tumor growth,metastasis, osteoporosis, restenosis, inflammation, maculardegeneration, diabetic retinopathy, sickle cell anemia, CNS disordersand rheumatoid arthritis in a mammal in need of such treatmentcomprising administering to said mammal an effective amount of acompound of Formula IV. Further provided is a pharmaceutical compositioncomprising a compound of Formula IV and one or more pharmaceuticallyacceptable carriers or diluents.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to compounds of Formula IV:

and pharmaceutically acceptable salts thereof, wherein

R¹, R², R³, R⁴ and R⁵ independently represent hydrogen, halogen, alkyl,aryl, aralkyl, heteroaryl or heteroarylalkyl;

R⁶, R⁷, R⁵ and R⁹ independently represent hydrogen, alkyl, hydroxyalkyl,aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, arylor aralkyl;

or R⁶ and R⁷ are taken together to form —(CH₂)_(p)—, where p is 2-8,while R⁵ and R⁹ are defined as above; or R⁵ and R⁹ are taken together toform —(CH₂)_(q)—, where q is 2-8, while R⁶ and R⁸ are defined as above;or R⁶ and R⁸ are taken together to form —(CH₂)_(r)—, while r is zero (abond), 1 or 2, while R⁷ and R⁹ are defined as above;

X represents oxygen, sulfur, —CH₂—, —NH—, —(C═O)NH— or —NH(C═O)—;

n is from 0 to 4;

m is from 0 to 4;

a is 0 or 1;

D represents oxygen;

v is 0 or 1;

R¹⁰, R¹¹, R¹² and R¹³ independently represent: hydrogen; hydroxy; alkyl;alkoxy; cycloalkyl; aryl, optionally substituted with one or more ofhalogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl,arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkoxyarylalkyl,monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl,dialkylaminoalkyl, alkanoyl; monoalkylamino; dialkylamino; aminoalkyl;monoalkylaminoalkyl; dialkylaminoalkyl; alkanoyl; heteroaryl having 5-14ring members, optionally substituted with one or more of halogen,hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy,aryloxy, alkylsulfonyl, alkylsulfinyl, alkoxyarylalkyl, monoalkylamino,dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,alkanoyl; or

wherein R¹⁷ and R¹⁸ together form —CH₂CH₂—O—, —O—CH₂CH₂—, —O—CH₂—O— or—O—CH₂CH₂—O—; or

R¹⁰ and R¹² are taken together to form —(CH₂)_(s)—, wherein s is 0 (abond) or 1 to 4, while R¹¹ and R¹³ are as defined as above; or R¹⁰ andR¹² are taken together to form a double bond when i is 0 and k is 1,while R¹¹ and R¹³ are as defined above; or R¹⁰ and R¹¹ are takentogether to form —(CH₂)_(t)—, wherein t is 2 to 8, while R¹² and R¹³ areas defined as above, or R¹² and R¹³ are taken together to form—(CH₂)_(u)— wherein u is 2 to 8, while R¹⁰ and R¹¹ are as defined asabove;

i is from 0 to 4;

j is from 0 to 4;

k is 0 or 1;

R¹⁴ is hydrogen or a functionality that acts as a prodrug (i.e.,converts to the active species by an endogenous biological process suchas an esterase, lipase, or other hydrolase), such as alkyl, aryl,aralkyl, dialkylaminoalkyl, 1-morpholinoalkyl, 1-piperidinylalkyl,pyridinylalkyl, alkoxy(alkoxy)alkoxyalkyl, or (alkoxycarbonyl)oxyethyl;

W is:

wherein:

Y is —N— or —CH—;

Z is —N— or —CH—;

R¹⁵ is hydrogen, halogen, alkyl, aryl or arylalkyl;

R¹⁶ is hydrogen, alkyl, haloalkyl or halogen;

R¹⁹ and R²⁰ are independently hydrogen, halogen or alkyl;

R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ are independently hydrogen, halogen, alkyl,alkoxy or aryl; and

o and p are independently 0, 1 or 2.

Where W is attached through a pyridine ring, the preferred point ofattachment is either ortho or meta to the pyridine nitrogen, and morepreferably ortho to the pyridine nitrogen.

Preferred compounds of the present invention are those of Formula IV,wherein R¹ and R² independently represent hydrogen, halogen,(C₁₋₆)alkyl, (C₁₋₆)aryl, (C₁₋₆)alkyl(C₆₋₁₀)aryl, (C₆₋₁₀)ar(C₁₋₆)alkyl,5-14 member heteroaryl, or 5-14 member heteroaryl(C₁₋₆)alkyl; orpreferably R¹ and R² independently represent hydrogen, methyl, ethyl,propyl, butyl, phenyl, benzyl or phenylethyl.

Also preferred are compounds of Formula IV, wherein R³, R⁴ and R⁵independently represent hydrogen, (C₁₋₆)alkyl, (C₆₋₁₀)aryl, or(C₆₋₁₀)ar(C₁₋₆) alkyl, preferably, R³, R⁴ and R⁵ are hydrogen or(C₁₋₄)alkyl.

Preferred compounds are those of Formula IV, wherein R⁶, R⁷, R⁵ and R⁹independently represent hydrogen or (C₁₋₄)alkyl.

Preferred compounds are those of Formula IV, wherein X is oxygen, —CH₂—,—(C═O)NH— or —HN(C═O)—, more preferably, X is oxygen, —CH₂— or—(C═O)NH—.

Also preferred are compounds of Formula IV, wherein W is

more preferably

wherein Y R¹⁵, R¹⁶, R¹⁹, R²⁰, R²⁷-R³¹ are as defined above;More preferably,

Y is —N— or —CH—;

R¹⁵ is hydrogen, halogen, (C₁₋₈)alkyl, (C₆₋₁₀)aryl or(C₆₋₁₀)aryl(C₁₋₈)alkyl;

R¹⁶ is hydrogen, (C₁₋₈)alkyl, halo(C₁₋₈)alkyl or halogen;

R¹⁹ and R²⁰ are hydrogen, halogen or (C₁₋₈)alkyl; and

R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ are hydrogen, halogen, (C₁₋₈)alkyl,(C₁₋₈)alkoxy, (C₆₋₁₀)aryl.

Further preferred compounds are those of Formula IV, wherein R¹⁰, R¹¹,R¹² and R¹³ independently represent hydrogen, hydroxy, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)ar(C₁₋₆)alkyl, (C₁₋₆)aminoalkyl,mono(C₁₋₄) alkylamino(C₁₋₆)alkyl, di-(C₁₋₄)alkylamino (C₁₋₆)alkyl,carboxy(C₁₋₆)alkyl, (C₁₋₆)alkoxy, mono-(C₁₋₄)alkylamino ordi-(C₁₋₄)alkylamino.

Also preferred are those compounds of Formula IV, wherein R¹⁰ and R¹²are taken together to form —(CH₂)_(s)— where s is zero or 1 to 4, andR¹¹ and R¹³ are each hydrogen.

Preferred compounds are those of Formula IV, wherein R¹⁰ and R¹¹ aretaken together to form —(CH₂)_(t), where t is 2 to 5 and R¹² and R¹³ areeach hydrogen.

Preferred compounds are also those wherein R¹² and R¹³ areindependently,

wherein:

b is from 0 to 4;

R³² is halogen, (C₁₋₈)alkyl, halo(C₁₋₈)alkyl, (C₁₋₈)alkoxy,(C₁₋₈)alkoxy(C₁₋₈)alkyl or halo(C₁₋₈)alkoxy;

R³³ is halogen;

R³⁴ is (C₁₋₈)alkyl, hydroxy or (C₁₋₈)alkoxy; or

two of R³², or two of R³³, or one of R³³ and R³⁴, when attached toadjacent carbon atoms, may together form a ring, wherein the ring formedis an aliphatic, aryl or heteroaryl ring, each of which may beoptionally substituted by one or more of halogen, hydroxy, cyano, alkyl,aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl,alkylsulfinyl, alkoxyarylalkyl, monoalkylamino, dialkylamino,aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl;monoalkylamino; dialkylamino; aminoalkyl; monoalkylaminoalkyl;dialkylaminoalkyl; alkanoyl.

Preferred compounds of the present invention include, but are notlimited to, those compounds wherein R¹² and R¹³ are independentlyselected from:

Additional preferred compounds of Formula IV, are those wherein R¹⁰ andR¹² are taken together to form a double bond where i is 0 and k is 1,and R¹¹ and R¹³ are each hydrogen.

Preferred compounds of the invention are also those wherein R¹⁰ is anoptionally substituted aryl or optionally substituted heteroaryl.

Additionally, preferred compounds of the invention may contain analkenyl carboxylic acid moiety.

Further preferred compounds are those of Formula IV, wherein i and j are0.

Preferred compounds are those of Formula IV, wherein k is 1.

Also preferred compounds are those of Formula IV, wherein R¹⁴ ishydrogen.

Preferred compounds are those of Formula IV, wherein i and j are eachzero; k is one; R¹⁰, R¹¹ and R¹² are each hydrogen; and R¹³ is hydrogen,C₁₋₆ alkyl, C₆₋₁₀ aryl or C₆₋₁₀ar(C₁₋₄) alkyl.

Preferred compounds of the present invention are those of Formula IVwherein:

R¹ is hydrogen or (C₁₋₄)alkyl, more preferably, hydrogen or methyl;

R², R³, R⁴, and R⁵ are hydrogen or (C₁₋₄)alkyl, more preferablyhydrogen;

R⁶, R⁷, R⁵ and R⁹ are preferably hydrogen or (C₁₋₄)alkyl, morepreferably hydrogen;

X is oxygen or —CH₂—;

n is 0 or 1;

m is 0 or 1;

R¹⁰, R¹¹, R¹² and R¹³ independently represent hydrogen, (C₁₋₆)alkyl or(C₆₋₁₀)ar(C₁₋₆)alkyl; or

one of the combination R¹⁰ or R¹¹, R¹² or R¹³, R¹⁰ and R¹² are takentogether to form —(CH₂)_(s)—, wherein s is 1 or 2 while the remainingR¹⁰—R¹³ are defined above;

i is 0 or 1;

j is 0 or 1;

k is 0 or 1;

R¹⁴ is hydrogen, C₁₋₆ alkyl or benzyl;

W is:

wherein:

Y is —N— or —CH—;

R¹⁵ is hydrogen, halogen, (C₁₋₈)alkyl, (C₆₋₁₀)aryl or(C₆₋₁₀)aryl(C₁₋₈)alkyl;

R¹⁶ is hydrogen, (C₁₋₈)alkyl, halo(C₁₋₈)alkyl or halogen;

R¹⁹ and R²⁰ are hydrogen, halogen or (C₁₋₈)alkyl; and

R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ are hydrogen, halogen, (C₁₋₈)alkyl,(C₁₋₈)alkoxy, (C₆₋₁₀)aryl.

Additionally preferred compounds of Formula IV are those wherein:

-   -   X is —(C═O)NH—;    -   n, m, a and v are each 0; and    -   R⁶, R⁷, R¹² and R¹³ are hydrogen.

Further preferred compounds of Formula IV are those wherein:

-   -   X is oxygen;    -   n and m are each 0;    -   a and v are each 1;    -   D is oxygen;    -   R⁶, R⁷, R⁸ and R⁹ are hydrogen.

Preferred compounds of Formula IV are also those wherein:

-   -   X is oxygen;    -   n, m and v are each 0;    -   a is 1; and    -   R⁶, R⁷, R¹² and R¹³ are hydrogen.

Further preferred compounds of Formula IV are also those wherein:

-   -   X is —CH₂—;    -   n, m and v are each 0;    -   a is 1; and    -   R⁶, R⁷, R¹² and R¹³ are hydrogen.

Examples of useful compounds of the present invention include:

-   3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;-   3-{5-[3-(2-pyridylamino)propoxy]indolyl}acetic acid;-   3-{2-methyl-5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;-   2-(trans-2-{5-[3-(2-pyridylamino)propoxy]indolyl}cyclopropyl)acetic    acid;-   3-(5-{2-[6-(methylamino)-2-pyridyl]ethoxy}indolyl)propanoic acid;-   2-benzyl-3-{5 [3-(2-pyridylamino)propoxy]indolyl}propanoic acid;-   2-methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;-   2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)pentanoic acid;-   2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)octanoic acid;-   3-[5-(3-{[benzylamino]carbonylamino}propoxy)indolyl]propanoic acid;-   3-[5-(2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-acetylamino)-indol-1-yl]-hexanoic    acid;-   3-(5-{2-[N-(4,5-dihydro-1H-imidazol-2-yl)-aminooxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic    acid;-   3-(5-{2-[guanidino-oxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic acid;-   3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoic    acid;-   3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(3-benzyloxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-p-tolyl-propionic    acid;-   3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-m-tolyl-propionic    acid;-   3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-O—    tolyl-propionic acid;-   3-biphenyl-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(3,5-dichloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(3,5-difluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(3-cyano-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(4-cyano-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(2-methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(3-methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(4-methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-quinolin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(3-chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-naphthalen-2-yl-3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(2-chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-naphthalen-1-yl-3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(4-fluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(3-trifluoromethyl-phenyl)-propionic    acid;-   3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(4-trifluoromethyl-phenyl)-propionic    acid;-   3-pyridin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylic    acid;-   3-(2,3-dihydro-benzofuran-5-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-benzo[1,3]dioxol-5-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-(5-methanesulfonyl-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyoxy]-indol-1-yl}-propionic    acid;-   3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-phenyl-propionic    acid;-   3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-quinolin-3-yl-propionic    acid;-   3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-pyridin-3-yl-propionic    acid;-   3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoic    acid;-   3-{5-[2-(2-methyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-ethyl]-indol-1-yl}-propionic    acid;-   3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionic    acid;-   3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-hexanoic    acid;-   3-phenyl-3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionic    acid;-   3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-propionic    acid;-   3-(5-Ethoxy-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-Pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-Pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylic    acid;-   6-(2-hydroxy-ethyl)-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylic    acid tert-butyl ester;-   3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-quinolin-3-yl-propionic    acid;

or a pharmaceutically acceptable salt, hydrate, solvate or prodrugthereof.

Particularly preferred compounds of the invention are:

-   3-(3-methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-quinolin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-pyridin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionic    acid;-   3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-quinolin-3-yl-propionic    acid;

or a pharmaceutically acceptable salt, hydrate, solvate or prodrugthereof.

It is also to be understood that the present invention is considered toinclude stereoisomers as well as optical isomers, e.g. mixtures ofenantiomers as well as individual enantiomers and diastereomers, whicharise as a consequence of structural asymmetry in selected compounds ofthe present series.

When any variable occurs more than one time in any constituent or inFormula IV, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The term “alkyl” as employed herein by itself or as part of anothergroup refers to both straight and branched chain radicals of up to 12carbons, preferably 1 to 8 carbons, such as methyl, ethyl, propyl,isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl,dodecyl.

The term “alkenyl” is used herein to mean a straight or branched chainradical of 2-20 carbon atoms, unless the chain length is limitedthereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, thealkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8carbon atoms in length most preferably from 2 to 4 carbon atoms inlength.

The term “alkoxy” is used herein to mean a straight or branched chainradical of 1 to 20 carbon atoms, unless the chain length is limitedthereto, bonded to an oxygen atom, including, but not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably thealkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8carbon atoms in length.

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic or bicyclic aromatic groups containing from 6 to 12carbons in the ring portion, preferably 6-10 carbons in the ringportion, such as phenyl, naphthyl or tetrahydronaphthyl.

The term Aaryloxy≅ as employed herein by itself or as part of anothergroup refers to monocyclic or bicyclic aromatic groups containing from 6to 12 carbons in the ring portion, preferably 6-10 carbons in the ringportion, bonded to an oxygen atom. Examples include, but are not limitedto, phenoxy, naphthoxy, and the like.

The term Aheteroaryl≅ as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroatoms (where examples of heteroaryl groups are: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl,isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,4H-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl and phenoxazinyl groups).

The term “aralkyl” or “arylalkyl” as employed herein by itself or aspart of another group refers to C₁₋₆alkyl groups as discussed abovehaving an aryl substituent, such as benzyl, phenylethyl or2-naphthylmethyl.

The term “cycloalkyl” as employed herein by itself or as part of anothergroup refers to cycloalkyl groups containing 3 to 9 carbon atoms.Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and cyclononyl.

The term “heterocycle” or “heterocyclyl” as used herein, except wherenoted, represents a stable 5- to 7-membered mono- or bicyclic or stable7- to 10-membered bicyclic heterocyclic ring system any ring of whichmay be saturated or unsaturated, and which consists of carbon atoms andfrom one to three heteroatoms selected from the group consisting of N, Oand S, and wherein the nitrogen and sulfur heteroatoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. Especially useful arerings containing one oxygen or sulfur, one to three nitrogen atoms, orone oxygen or sulfur combined with one or two nitrogen atoms. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of suchheterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, chromanyl,benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl,benzo[b]thiophenyl, benzo[2,3-c]1,2,5-oxadiazolyl, benzoxazolyl, furyl,tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, andoxadiazolyl. Morpholino is the same as morpholinyl.

The term “halogen” or “halo” as employed herein by itself or as part ofanother group refers to chlorine, bromine, fluorine or iodine withfluorine being preferred.

The term “monoalkylamino” as employed herein by itself or as part ofanother group refers to an amino group which is substituted with onealkyl group having from 1 to 6 carbon atoms.

The term “dialkylamino” as employed herein by itself or as part ofanother group refers to an amino group which is substituted with twoalkyl groups, each having from 1 to 6 carbon atoms.

The term “hydroxyalkyl” as employed herein refers to any of the abovealkyl groups substituted by one or more hydroxyl moieties.

The term “carboxyalkyl” as employed herein refers to any of the abovealkyl groups substituted by one or more carboxylic acid moieties.

The term “haloalkyl” as employed herein refers to any of the above alkylgroups substituted by one or more chlorine, bromine, fluorine or iodinewith fluorine and chlorine being preferred, such as chloromethyl,iodomethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 2-chloroethyl.

The term Ahaloalkoxy≅ as used herein refers to any of the abovehaloalkyl groups bonded to an oxygen atom, such as trifluoromethoxy,trichloromethoxy, and the like.

The present invention is also directed to method for preparing compoundsof Formula IV, comprising:

-   -   reacting a compound of Formula V:        or a salt, hydrate or solvate thereof, wherein R¹, R², R³, R⁴,        R⁵, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, i, j and k are as defined as above,    -   with the compound of Formula VI or Formula X:        or a salt, hydrate or solvate thereof, wherein R¹⁵ is as defined        above, to form the compound Formula IV.

The present invention is also directed to method for preparing compoundsof Formula IV, comprising:

-   -   reacting a compound of Formula V:        or a salt, hydrate or solvate thereof, wherein R¹, R², R³, R⁴,        R⁵, R¹⁰, R¹¹, R^(12i), R¹³, R¹⁴, i, j and k are as defined as        above,    -   with the compound of Formula IX:        or a salt, hydrate or solvate thereof, wherein R¹⁶, R¹⁹ and R²⁰        are as defined above, and R³⁵ is alkyl, aryl, alkylaryl or        arylalkyl, followed by removal of the R³⁵ containing protecting        group to form the compound Formula IV.

The present invention is also directed to a method for preparingcompounds of Formula IV, comprising reacting a compound of Formula V:

or a salt, hydrate or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R¹⁰,R¹¹, R^(12i), R¹³, R¹⁴, i, j and k are as defined above,

-   -   with the compound of Formula VII:        or a salt, hydrate or solvate thereof, wherein R⁶, R⁷, R⁸, R⁹,        R¹⁶, m and n are as defined above, to form the compound of        Formula IV.

The present invention is also directed to a method for preparingcompounds of Formula IV, comprising reacting a compound of Formula VIII:

or a salt, hydrate or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, i, j, k, m and n are as defined inclaim 1, with R¹⁵NCO, where R¹⁵ is as defined in claim 1, to form asubstituted indole compound of claim 1.

The compounds of the present invention may be prepared by the generalprocedures outlined in Schemes I-VII (below), where R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, n, m, i, j, X and W are asdefined above. Additional R-groups, not defined above, but usedthroughout the schemes below are defined as indicated below:

-   -   R¹⁷, R¹⁸, R¹⁹, R²⁰, R²⁴ and R²⁵ are independently hydrogen,        halogen or alkyl;    -   R²¹ is trialkylsilyl or alkylorthoformate; preferably        trimethylsilyl or (C₁₋₆)alkylorthoformate;    -   R²² is alkyl, aryl, heteroaryl, or an aliphatic ring system;    -   R²³ is a protecting group such as a trialkylsilyl, such as        trimethylsilyl, triisopropylsilyl; benzyl or sulfonyl;    -   R²⁶ is hydrogen, alkyl, aryl, heteroaryl, or an aliphatic ring        system;    -   R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ are independently hydrogen, halogen,        alkoxyaryl or an aliphatic ring system;    -   R³⁰ and R³¹ are independently hydrogen, alkyl, aryl or an        aliphatic ring system;    -   R³² is halogen, alkyl, haloalkyl, alkoxy, alkoxyalkyl or        haloalkoxy;    -   R³³ is halogen, alkyl, haloalkyl, alkoxy, alkoxyalkyl or        haloalkoxy, and is preferably halogen;    -   R³⁴ and R³⁵ are independently alkyl, hydroxy, alkoxy, aryl,        alkylaryl or arylalkyl; and    -   o and p are 0, 1 or 2.

Scheme Ia, Ib, Ic, Id and Ie outline the synthetic steps to producecompounds of the present invention where X is O and W is

In Scheme Ia, 2-chloropyridine N-oxide derivative 1 is refluxed withaminoalkyl alcohol 2 in the presence of a base, such as sodiumbicarbonate, and a suitable solvent, such as tert-amyl alcohol, to givecompound 3. Compound 3 is then converted to pyridinyl aminoalkyl alcohol4 using standard reduction conditions. Preferred conditions includetreating compound 3 with cyclohexene in the presence of a catalyst, suchas palladium on carbon, and a solvent, such as ethanol.

In Scheme Ib, a 2-amino-5-methylpyridine analogue 5 is first protectedwith a tert-butyloxycarbonyl (Boc) group using conditions well known inart (Greene, T. W. and Wuts, P. G. M., Protective Groups in OrganicSynthesis, 2^(nd) edition, John Wiley and Sons, Inc., New York (1991)),followed by treatment with an alkyl halide, such as iodomethane, in thepresence of a base, such as sodium hydride, and a solvent, such astetrahydrofuran (THF) or dimethylformamide (DMF), to give compound 6.Converting compound 6 to compound 7 is accomplished by reacting compound6 with a base, such as lithium diisopropylamide (LDA), and diethylcarbonate in a solvent, such as tetrahydrofuran (THF). The Bocprotecting group of compound 7 is removed by standard procedures wellknown in the art (Greene, T. W. and Wuts, P. G. M., supra), such astrifluoroacetic acid in methylene chloride. The ester is then reduced bystandard conditions, such as lithium aluminum hydride (LAH) intetrahydrofuran (THF), to give compound 8. Alternatively, compound 7 canbe treated with a reducing agent, such as lithium borohydride in asolvent such as tetrahydrofuran to give compound 9.

In Scheme Ic, Compound 10 (Miller, H.; Manley, P. J., PCT Int. Appl.2000, 40 pp. WO 00/33838) is treated with a reducing agent such aslithium borohydride, in a solvent such as tetrahydrofuran, to givecompound 11.

In Scheme 1d, 3-hydroxy-6-methyl-2-nitropyridine derivative 12a isreduced under suitable conditions, such as hydrogenation in the presenceof palladium catalyst, with a solvent, such as ethanol, to give compound12b. Reaction of compound 12b (L. Savelon, et. al., Biorganic andMedicinal Chemistry, 6, 133, (1998)) with 2-haloacid chloride 12c, suchas chloroacetyl chloride, in the presence of base, such as sodiumbicarbonate, in suitable solvents, such as water and 2-butanone, givescompound 13. Reduction of compound 13 with suitable reagent, such aslithium aluminum hydride, in a suitable solvent, such as THF, givescompound 14. Compound 14 is protected using suitable conditions, tointroduce a protecting group, such as Boc, to give compound 15 (Greene,T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 2^(nd)edition, John Wiley and Sons, Inc., New York (1991)). Compound 15 isalkylated under suitable conditions, such as deprotonation with base,such as LDA, followed by reaction with alkylating reagent, such asdialkylcarbonate, to produce compound 16. Reduction of compound 16 isachieved with suitable reducing reagent, such as lithium borohydride ina solvent such as tetrahydrofuran, to give compound 17.

In Scheme Ie, the protected indole 18 (P is protecting group), such as5-benzyloxyindole, is reacted with a base, such as sodium hydride, andhaloalkylcarboxyl ester 19, in a suitable solvent, such asN,N-dimethylformamide (DMF), to generate compound 20. The protectinggroup is removed by conditions well known in the art (Greene, T. W. andWuts, P. G. M., supra), to give compound 21. For example, deprotectionof benzyl ether is achieved through catalytic hydrogenation usingpalladium on carbon as a catalyst in a solvent, such as ethanol ortetrahydrofuran. Compound 21 is coupled to compounds 4 using a Mitsunobucoupling procedure (Mitsunobu, O., Synthesis, 1 (1981)) to give compound22. Preferred coupling conditions include using a trialkylphosphine ortriarylphosphine, such as triphenylphosphine or tri-n-butylphosphine, ina suitable solvent, such as tetrahydrofuran or methylene chloride, andan azodicarbonyl reagent, such as diethyl azodicarboxylate, diisopropylazodicarboxylate or 1,1′-(azodicarbonyl)dipiperidine. Compound 22 isoptionally converted to compound 23 by a standard procedure, such assodium hydroxide in a solvent, such as methanol and water.Alternatively, compound 21 is coupled to compounds 8 or 11 using aMitsunobu coupling procedure (Mitsunobu, O., Synthesis, 1 (1981)) togive compound 24. Preferred coupling conditions include using atrialkylphosphine or triarylphosphine, such as triphenylphosphine ortri-n-butylphosphine, in a suitable solvent, such as tetrahydrofuran ormethylene chloride, and an azodicarbonyl reagent, such as diethylazodicarboxylate, diisopropyl azodicarboxylate or1,1′-(azodicarbonyl)dipiperidine. Compound 24 is optionally deprotectedwhen Z=Boc with standard deprotection conditions (Greene, T. W. andWuts, P. G. M., supra), followed by and optional hydrolysis usingstandard conditions such as sodium hydroxide in a solvent, such asmethanol and water to give compound 25.

Scheme II outlines the synthetic steps to produce compounds of thepresent invention where X is O and W is

Compound 21 is coupled with benzyloxycarbonyl (Cbz) protected aminoalcohol 26 using a Mitsunobu coupling procedure (Mitsunobu, O.,Synthesis, 1 (1981)) to give compound 27. Preferred coupling conditionsinclude using a trialkylphosphine or triarylphosphine, such astriphenylphosphine or tri-n-butylphosphine, in a suitable solvent, suchas tetrahydrofuran or methylene chloride, and an azodicarbonyl reagent,such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or1,1′-(azodicarbonyl)dipiperidine. Compound 27 is deprotected usingstandard deprotection conditions such as hydrogenation using palladiumon carbon as a catalyst in solvents such as ethanol or tetrahydrofuran,to give compound 28. Compound 28 is treated with isocyanate analogue 29in a solvent such as acetonitrile to give compound 30. Compound 30 isoptionally converted to acid 31 by a standard hydrolysis procedure suchas sodium hydroxide in a solvent, such as methanol and water.

Scheme IIIa, IIIb and IIIc outline the synthetic steps to producecompounds of the present invention where X is O, and W is

In Scheme IIIa, aryl halides 32 are reacted with protected acetylenes33, such as trimethylsilylacetylenes or trialkyloxypropynes under crosscoupling conditions with suitable reagents, such as palladium (II) andcopper iodide, in the presence of base, such as triethylamine, to giveprotected arylacetylene compounds 34 (Sonogashira, K., Tetrahedron Lett.1975, 50, 4467-70). Removal of the trimethylsilyl group of compound 34is achieved under various conditions, such as tetrabutylammoniumfluoride or base, to give compound 35 (Greene, T. W. and Wuts, P. G. M.,Protective Groups in Organic Synthesis, 2^(nd) edition, John Wiley andSons, Inc., New York (1991)). Treatment of compound 35 with a suitablereagent, such as alkyl haloformate, in the presence of base, such asLDA, or butyllithium, gives compound 36. Alternatively, the aryltriethoxypropyne 34 can be treated with a suitable acid, such asp-toluenesulfonic acid, to give compound 36.

In Scheme IIIb, aliphatic acetylene 37 or aromatic acetylene 37(synthesized using methodology describe in Scheme IIIa) is treated withalkylchloroformate in the presence of a catalyst such ascarbonylchlorobis-(triphenylphosphine)-rhodium(I), in a solvent such astoluene, to give compound 38.

In Scheme IIIc, aliphatic or aromatic aldehyde 39 is treated withsuitable reagents, such carbontetrabromide and triphenylphosphine, togive compound 40. Treatment of the compound 40 with suitable base, suchas n-butyllithium, gives compound 41. Reaction of compound 41 withsuitable base, such as LDA, or n-butyllithium (Corey, E. J.; Fuchs, P.L., Tetrahedron Lett. (1972), (36), 3769-72), followed by alkylhaloformate, such as ethyl chloroformate, generates compound 42.

In Scheme IIId, aromatic or aliphatic ketones 43 are treated with base,such as sodium hydride, in a solvent such as tetrahydrofuran, anddialkylcarbonate or alkylchloroformate to give compound 44. Compound 44is then treated with triphenylphosphine oxide andtrifluoromethanesulfonate anhydride in the presence of a base, such astriethylamine to give compound 42 (Hendrickson, J., Synthesis, 1989,217).

In Scheme IIIe, compound 9 or 11 or 17 is coupled with a3-methyl-4-nitro-phenol derivative 45 using a Mitsunobu couplingprocedure (Mitsunobu, O., Synthesis, 1 (1981)) to give compounds 46.Preferred coupling conditions include using a trialkylphosphine ortriarylphosphine, such as triphenylphosphine or tri-n-butylphosphine, ina suitable solvent, such as tetrahydrofuran or methylene chloride, andan azodicarbonyl reagent, such as diethyl azodicarboxylate, diisopropylazodicarboxylate or 1,1′-(azodicarbonyl)dipiperidine. Compound 46 can betreated with pyrrolidine and dimethoxymethyl dimethylamine to give thecorresponding enamine, followed by standard reduction conditions such ashydrogenation in the presence of a catalyst, such as palladium oncarbon, and a solvent such as ethanol, to give compound 47 (Batcho, A.,Batcho, Andrew D.; Leimgruber, Willy., Org. Synth. 1985, 63, 214-25).Compound 47 is then reacted with an appropriate substituted propiolate36 or 42, in the presence of a base, such as cesium fluoride ortetrabutylammonium fluoride, in a solvent such as THF or DMF, to givecompound 48. Alternatively, compound 47 is treated with substitutedvinylhalide ester 38 using a catalyst such ascarbonylchlorobis-(triphenylphosphine)-rhodium(I) in a solvent such astoluene to give compound 48.

Compound 48 is then optionally reduced through treatment such ashydrogenation, in the presence of a catalyst, such as palladium oncarbon, followed by Boc removal which can be carried out by deprotectionconditions such as heating the neat compound to 180° C. to give compound49a or 49b. Compound 49a or 49b can then optionally be hydrolyzed in thepresence of a base, such as potassium hydroxide in a solvent such asmethanol and water, to give compound 50a or 50b.

Scheme IVa, IVb, IVc and IVd outline the synthetic steps to producecompounds of the present invention where X is C, and W is

In Scheme IVa, 5-haloindole derivative 51 is protected under standardprotection conditions with triisopropylsilylchloride, in the presence ofa base, such as lithium hexamethyldisilazane, to give protected compound52. Compound 52 is coupled with cyanoalkyl zinc halide 53, such as3-cyanopropyl zinc bromide, in the presence of a catalyst, such astetrakis(triphenylphosphine)palladium(0), to afford compound 54.Compound 54 is treated under suitable conditions, such as alkylmagnesium halides, followed by quenching with water to give compound 55.Finally, the compound 55 is condensed with substituted2-amino-pyridine-3-carbaldehyde 56, in the presence of a base, such asL-proline, in a solvent, such as ethanol, to give a mixture of compound57 and 58.

In Scheme IVb, compound 58 is treated with substituted propynoic acidester 36 or 42, such as phenyl propynoic acid ethyl ester, in thepresence of a base, such as tetrabutylammonium fluoride or cesiumfluoride, in a solvent such as tetrahydrofuran, to give compound 59 asan E/Z isomeric mixture. Compound 59 is reduced under standard reductionconditions such as hydrogenation, in the presence of a catalyst, such aspalladium on carbon, with a solvent, such as methanol, to give compound60. Optional hydrolysis of compound 60 under suitable conditions, suchas aqueous lithium hydroxide or sodium hydroxide, in a suitable solvent,such as methanol or THF, gives compound 61.

In Scheme IVc, compound 57 is deprotected under suitable conditions withreagents, such as tetrabutylammonium fluoride, in a solvent, such astetrahydrofuran, to give compound 62. Compound 62 is then treated withalkyl halide 19 such as 3-bromo-propionic acid ethyl ester, in thepresence of a base, such as sodium hydride, in a solvent, such as DMF,to give compound 63. Compound 63 is reduced under standard reductionconditions such as hydrogenation, in the presence of a catalyst, such aspalladium on carbon, with a solvent, such as methanol or ethyl acetate,to give compound 64. Optional hydrolysis of compound 64 is done undersuitable conditions, such as aqueous lithium hydroxide or sodiumhydroxide, in a suitable solvent, such as methanol or THF, to givecompound 65.

In Scheme IVd, compound 57 is treated with substituted propynoic acidester 36 or 42, such as phenyl propynoic acid ethyl ester, in thepresence of a base, such as tetrabutylammonium fluoride or cesiumfluoride, in a solvent such as tetrahydrofuran, to give compound 66 asan E/Z isomeric mixture. Compound 66 is reduced under standard reductionconditions such as hydrogenation, in the presence of a catalyst, such aspalladium on carbon, with a solvent, such as methanol or ethyl acetate,to give a mixture of compound 67 and 68. Without separation, optionalhydrolysis of the mixture of compounds 67 and 68 under basic conditions,such as aqueous lithium hydroxide or sodium hydroxide solution in THF ormethanol, to give compound 69 as the major product, with compound 70 asthe minor product.

Scheme V outline the synthetic steps to produce compounds of the presentinvention where X is O and W is

In Scheme V, protected 5-hydroxylindole compound 18 is treated withsubstituted propynoic acid ester 36 or 42, such as phenyl propynoic acidethyl ester, in the presence of a base, such as tetrabutylammoniumfluoride or cesium fluoride, in solvent such as tetrahydrofuran, to givecompound 71 as an E/Z isomeric mixture. Compound 71 is reduced understandard reduction conditions such as hydrogenation, in the presence ofa catalyst, such as palladium on carbon, with a solvent, such asmethanol or ethyl acetate, to give compound 72. Compound 72 is coupledwith compound II or 17 using a Mitsunobu coupling procedure (Mitsunobu,O., Synthesis, 1 (1981)) to give compound 73. Preferred couplingconditions include using a trialkylphosphine or triarylphosphine, suchas triphenylphosphine or tri-n-butylphosphine, in a suitable solvent,such as tetrahydrofuran or methylene chloride, and an azodicarbonylreagent, such as diethyl azodicarboxylate, diisopropyl azodicarboxylateor 1,1′-(azodicarbonyl)dipiperidine. Deprotection of compound 73 iscarried out with copper (I) trifluoremethanesulfonate, in a solvent,such as DMF in toluene at 200° C. to give compound 74. Optionalhydrolysis of compound 74 under basic conditions, such as aqueouslithium hydroxide or sodium hydroxide in THF or methanol, gives compound75.

Scheme VI outline the synthetic steps to produce compounds of thepresent invention where X is NR, R6 and R7 are combined to form acarbonyl, and W is

In Scheme VI, 5-nitroindole derivative 76 is treated with alkyl halides19 in the presence of base, such as sodium hydride, to give compound 77.Compound 77 is reduced under standard conditions, such as hydrogenationwith a catalyst, such as palladium on activated carbon, with a suitablesolvent, such as ethanol or methanol, to compound 78. Compound 10 ishydrolyzed under suitable conditions, such as sodium hydroxide to givethe free acid, followed by Boc deprotection which is carried out usingstandard deprotection conditions (T. W. Greene, Protective groups inorganic synthesis, 1999 John Wiley & Sons, Inc.) to give compound 79.Compound 79 is then coupled with compound 78 under typical amidecoupling conditions, such asbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophophate,diisopropylethylamine, and dimethylformamide, to give compound 80.Optionally, compound 80 is hydrolyzed under typical conditions, such assodium hydroxide, with suitable solvent, such as water and methanol, togive compound 81.

Scheme VII outline the synthetic steps to produce compounds of thepresent invention where X is O, D is O, v is 1, and W is

In Scheme VII, 3-methyl-4-nitrophenol derivative 45 is coupled to analiphatic alcohol 82 using standard Mitsunobu coupling procedure(Mitsunobu, O., Synthesis, 1 (1981)) to give compound 83. Preferredcoupling conditions include using a trialkylphosphine ortriarylphosphine, such as triphenylphosphine or tri-n-butylphosphine, ina suitable solvent, such as tetrahydrofuran or methylene chloride, andan azodicarbonyl reagent, such as diethyl azodicarboxylate, diisopropylazodicarboxylate or 1,1′-(azodicarbonyl)dipiperidine. Compound 83 istreated with pyrrolidine and dimethoxymethyl dimethylamine analogues togive the corresponding enamine 84, followed by standard reductionconditions such as hydrogenation in the presence of a catalyst, such aspalladium on carbon, and a solvent such as ethanol, to give compound 85(Batcho, A., Batcho, Andrew D.; Leimgruber, Willy., Org. Synth. 1985,63, 214-25). Compound 85 is reacted with a substituted propiolate 36 or42, in the presence of a weak base to yield the corresponding alkene 86,as an E/Z mixture. Preferred conditions include the treatment ofcompound 85 with tetrabutylammonium fluoride in tetrahydrofuran.Compound 86 is deprotected and reduced using standard conditions, suchas hydrogenation, using a catalyst such as palladium on carbon, in asuitable solvent, such as ethanol, to give compound 87. Compound 87 istreated with N-hydroxyphthalimide using standard Mitsunobu couplingprocedure (Mitsunobu, O., Synthesis, 1, 1981) to give compound 88.Preferred coupling conditions include using a trialkylphosphine ortriarylphosphine, such as triphenylphosphine or tri-n-butylphosphine, ina suitable solvent, such as tetrahydrofuran or methylene chloride, andan azodicarbonyl reagent, such as diethyl azodicarboxylate, diisopropylazodicarboxylate or 1,1′-(azodicarbonyl)dipiperidine. Deprotection ofcompound 88 is carried out in the presence of a primary amine, preferredconditions include the use of methylamine in tetrahydrofuran, to givecompound 89. Alkylation of compound 89 with a corresponding pyrazole,such as 1H-pyrazole-1-carboxamide hydrochloride or2-(3,5-dimethylpyrazolyl)-4,5-dihydroimidizole hydrobromide in methanolgives compound 90. Optional hydrolysis of the compound 90 using lithiumhydroxide in the presence of water afforded compound 91.

Compounds of the present invention can be tested for the ability toinhibit or antagonize α_(v)β₃ or α_(v)β₅ cell surface receptors byassays known to those of ordinary skill in the art. Such assays aredescribed in Example 58 herein.

The present invention also provides a method of treating α_(v)β₃integrin- or α_(v)β₅ integrin-mediated conditions by selectivelyinhibiting or antagonizing α_(v)β₃ and α_(v)β₅ cell surface receptors,which method comprises administering a therapeutically effective amountof a compound selected from the class of compounds depicted by FormulaIV, wherein one or more compounds of Formula IV is administered inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants and if desired other activeingredients.

More specifically, the present invention provides a method forinhibition of the α_(v)β₃ cell surface receptor. Most preferably, thepresent invention provides a method for inhibiting bone resorption,treating osteoporosis, inhibiting humoral hypercalcemia of malignancy,treating Paget=s disease, inhibiting tumor metastasis, inhibitingneoplasia (solid tumor growth), inhibiting angiogenesis including tumorangiogenesis, treating diabetic retinopathy, age-related maculardegeneration, retinopathy of prematurity and other neo-vascular eyediseases, inhibiting arthritis, psoriasis and periodontal disease, andinhibiting smooth muscle cell migration including neointimal hyperplasiaand restenosis.

The present invention also provides a method for inhibition of theα_(v)β₅ cell surface receptor. Most preferably, the present inventionprovides a method for inhibiting angiogenesis associated withpathological conditions such as inflammatory disorders such as immuneand non-immune inflammation, chronic articular rheumatism and psoriasis,disorders associated with inappropriate or inopportune invasion ofvessels such as restenosis, capillary proliferation in atheroscleroticplaques and osteoporosis, and cancer associated disorders, such as solidtumors, solid tumor metastases, angiofibromas, retrolental fibroplasia,hemangiomas, Kaposi sarcoma and similar cancers which requireneovascularization to support tumor growth. The present invention alsoprovides a method for treating eye diseases characterized byangiogenesis, such as diabetic retinopathy, age-related maculardegeneration, presumed ocular histoplasmosis, retinopathy ofprematurity, and neovascular glaucoma.

The compounds of the present invention are useful in treating cancer,including tumor growth, metastasis and angiogenesis. For example,compounds of the present invention can be employed to treat breastcancer and prostate cancer.

The compounds of the present invention are also useful in the treatmentof sickle cell anemia. α_(v)β₃ integrin has recently been implicated inthe mechanism of adhesion of sickled red blood cells (RBCs) to vascularstructures within the circulatory system of those suffering from sicklecell anemia. Adhesion of RBC=s is responsible for the reoccurringepisodes of painful vasocclusive crisis and multiple organ damage. (Kaulet al., Blood 95(2):368-373 (2000)). Monoclonal antibodies which bind toα_(v)β₃ have been shown to inhibit the adhesion of sickled RBCs in theex vivo mesocecum vasculature of the rat. By blocking α_(v)β₃ integrinwhich assists in adhesion of sickled cells to vascular components, areduction in the harmful affects of sickle cell anemia is realized.

The compounds of the present invention are also useful in the treatmentof central nervous system (CNS) related disorders. Treatment of such CNSrelated disorders includes, but is not limited to: treating orpreventing neuronal loss associated with stroke, ischemia, CNS trauma,hypoglycemia, and surgery, as well as treating neurodegenerativediseases including Alzheimer's disease, and Parkinson's disease,treating or preventing the adverse consequences of the overstimulationof the excitatory amino acids, as well as treating schizophrenia,anxiety, convulsions, chronic pain, psychosis, including anesthesia, andpreventing opiate tolerance.

Studies have shown that there is a correlation between the activity of∀4 integrin and the establishment of inflammatory lesions in the CNS.Brocke, S. et al., Proc. Natl. Acad. Sci. USA 96:6896-6901 (1999).Specifically, antibodies directed against CD44 and ∀4 integrin couldinterfere in several ways with the establishment of inflammatory lesionsin the CNS and thus prevent experimental autoimmune encephalomyelitis(EAE), an inflammatory disease of the CNS similar to multiple sclerosis.Brocke at 6899.

Relton and co-workers have also shown that inhibition of ∀4 integrinactivity protects the brain against ischemic brain injury, therebyimplicating ∀4 integrin as a factor in acute brain injury. Relton, etal., Stroke 32(1):199-205 (2001).

The compounds of the present invention may be administered in aneffective amount within the dosage range of about 0.01 mg/kg to about300 mg/kg, preferably between 1.0 mg/kg to 100 mg/kg body weight.Compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three or four times daily.

The pharmaceutical compositions of the present invention can beadministered to any animal that can experience the beneficial effects ofthe compounds of the invention. Foremost among such animals are humans,although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention can beadministered by any means that achieve their intended purpose. Forexample, administration can be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.Alternatively, or concurrently, administration can be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

In addition to the pharmacologically active compounds, thepharmaceutical preparations of the compounds can contain suitablepharmaceutically acceptable carriers comprising excipients andauxiliaries that facilitate processing of the active compounds intopreparations that can be used pharmaceutically. The pharmaceuticalpreparations of the present invention are manufactured in a manner thatis, itself, known, for example, by means of conventional mixing,granulating, dragee-making, dissolving, or lyophilizing processes. Thus,pharmaceutical preparations for oral use can be obtained by combiningthe active compounds with solid excipients, optionally grinding theresulting mixture and processing the mixture of granules, after addingsuitable auxiliaries, if desired or necessary, to obtain tablets ordragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample, lactose or sucrose, mannitol or sorbitol, cellulosepreparations and/or calcium phosphates, for example, tricalciumphosphate or calcium hydrogen phosphate, as well as binders, such asstarch paste, using, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents can be added,such as the above-mentioned starches and also carboxymethyl-starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example silica, talc, stearicacid or salts thereof, such as magnesium stearate or calcium stearate,and/or polyethylene glycol. Dragee cores are provided with suitablecoatings, that, if desired, are resistant to gastric juices. For thispurpose, concentrated saccharide solutions can be used, which mayoptionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethyleneglycol, and/or titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. In order to produce coatings resistant togastric juices, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, areused. Dye stuffs or pigments can be added to the tablets or drageecoatings, for example, for identification or in order to characterizecombinations of active compound doses.

Other pharmaceutical preparations that can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active compounds in the form of granules thatmay be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids such as fatty oils or liquidparaffin. In addition, stabilizers may be added.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for examplewater-soluble salts and alkaline solutions. Alkaline salts can includeammonium salts prepared, for example, with Tris, choline hydroxide,bis-Tris propane, N-methylglucamine, or arginine. In addition,suspensions of the active compounds as appropriate oily injectionsuspensions can be administered. Suitable lipophilic solvents orvehicles include fatty oils, for example, sesame oil, or synthetic fattyacid esters, for example, ethyl oleate or triglycerides or polyethyleneglycol-400 (the compounds are soluble in PEG-400). Aqueous injectionsuspensions can contain substances that increase the viscosity of thesuspension, for example sodium carboxymethyl cellulose, sorbitol, and/ordextran. Optionally, the suspension may also contain stabilizers.

The compounds of the present invention may be administered to the eye inanimals and humans as a drop, or within ointments, gels, liposomes, orbiocompatible polymer discs, pellets or carried within contact lenses.The intraocular composition may also contain a physiologicallycompatible ophthalmic vehicle as those skilled in the art can selectusing conventional criteria. The vehicles may be selected from the knownophthalmic vehicles which include but are not limited to water,polyethers such polyethylene glycol 400, polyvinyls such as polyvinylalcohol, povidone, cellulose derivatives such as carboxymethylcellulose,methylcellulose and hydroxypropyl methylcellulose, petroleumnderivatives such as mineral oil and white petrolatum, animal fats suchas lanolin, vegetable fats such as peanut oil, polymers of acrylic acidsuch as carboxylpolymethylene gel, polysaccharides such as dextrans andglycosaminoglycans such as sodium chloride and potassium, chloride, zincchloride and buffer such as sodium bicarbonate or sodium lactate. Highmolecular weight molecules can also be used. Physiologically compatiblepreservatives which do not inactivate the compounds of the presentinvention in the composition include alcohols such as chlorobutanol,benzalknonium chloride and EDTA, or any other appropriate preservativeknown to those skilled in the art.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered and obvious to those skilled in the art are within thespirit and scope of the invention.

EXAMPLE 1 3-{5-[3-(2-Pyridylamino)propoxy]indolyl}propanoic acidammonium salt

a). 2-(3-Hydroxypropyl)aminopyridine N-oxide

A mixture of 2-chloropyridine-N-oxide hydrochloride (3.32 g, 20 mmol),3-amino-1-propanol (3.06 mL, 40 mmol), NaHCO₃ (8.4 g, 100 mmol) intert-amyl alcohol (20 mL) was heated to reflux. After stirringovernight, the reaction mixture was cooled, diluted with methylenechloride (100 mL), and suction filtered to remove the insolublematerials. The filtrate was concentrated and reconcentrated frommethylene chloride twice. The residue was recrystallized from ethylacetate and hexane, collected by filtration, washed with ethyl acetate,and dried under high vacuum to give the title compound as a pale yellowsolid (3.2 g, 95%). ¹H-NMR (400 MHz, CDCl₃) * 8.07 (d, J=6.5 Hz, 1H),7.32 (br s, 1H), 7.21 (t, J=8.6 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 6.53(t, J=6.7 Hz, 1H), 3.75 (t, J=5.8 Hz, 2H), 3.47 (q, J=6.2 Hz, 2H), 1.86(t, J=6.0 Hz, 2H).

b). 2-(3-Hydroxypropyl)aminopyridine

A mixture of 2-(3-hydroxypropyl)aminopyridine N-oxide (3.0 g, 17.9mmol), as prepared in the preceding step, cyclohexene (10 mL, 100 mmol),and 10% palladium(0) on carbon (300 mg) in ethanol (50 mL) was heated toreflux. After two days, the reaction mixture was cooled. The catalystwas removed by filtration through Celite and the filtrate wasconcentrated. The residue was purified by flash column chromatography(silica gel, 5% methanol in methylene chloride) to give the titlecompound as a colorless oil (2.4 g, 88%). ¹H-NMR (400 MHz, CDCl₃) * 8.02(d, J=5.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 6.54 (d, J=6.0 Hz, 1H), 6.39(t, J=8.0 Hz, 1H), 4.69 (br s, 2H), 3.65 (t, J=5.5 Hz, 2H), 3.53 (q,J=5.9 Hz, 2H), 1.77 (t, J=5.6 Hz, 2H).

c). Ethyl 3-(5-benzyloxy)indolyl]propanoate

A solution of 5-benzyloxyindole (1.30 g, 5.82 mmol) was dissolved inanhydrous N,N-dimethylformamide (25 mL) under nitrogen and treated witha 60% suspension of sodium hydride in mineral oil (0.60 g, 15 mmol).After stirring 1 hour (Ah≅) at ambient temperature, the reaction wastreated with ethyl 3-bromopropionate (1.00 mL, 6.96 mmol) and stirred anadditional 18 h. The reaction was then treated with additional sodiumhydride (0.3 g, 7.5 mmol), stirred 2 more hours and the solvent removedin vacuo. The crude product was dissolved in methylene chloride, washedwith 10% aqueous HCl, water, and brine, dried over anhydrous sodiumsulfate, and filtered. The filtrate was evaporated and the residuepurified by flash column chromatography (1:1 methylene chloride:ethylacetate eluant) giving the title compound as a yellow oil (0.96 g, 51%).¹H NMR (400 MHz, CDCl₃) * 7.47 (br d, 2H, J=7.2 Hz), 7.37 (m, 2H), 7.32(m, 1H), 7.24 (br d, 1H, J=8.8 Hz), 7.15 (d, 1H, J=2.4 Hz), 7.10 (m,1H), 6.96 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.38 (m, 1H), 5.09 (s, 2H), 4.44(t, 2H, J=6.9 Hz), 4.21 (q, 2H, J=7.1 Hz), 2.92 (t, 2H, J=6.9 Hz), 1.26(m, 3H).

d). Ethyl 3-(5-hydroxyindolyl)propanoate

A solution of the product of the preceding step (0.94 g, 2.90 mmol) and10% palladium(0) on carbon (97 mg) in reagent ethanol (40 mL) wasstirred under hydrogen at ambient pressure and temperature for 18 h. Thereaction was filtered over Celite, and the evaporated filtrate purifiedby flash column chromatography (10% ethyl acetate in methylene chlorideeluant) giving the title compound as a colorless oil (0.36 g, 53%). ¹HNMR (400 MHz, CDCl₃) * 7.18 (d, 1H, J=8.7 Hz), 7.10 (d, 1H, J=3.0 Hz),7.01 (d, 1H, J=1.9 Hz), 6.78 (dd, 1H, J=8.7 Hz, 2.2 Hz), 6.34 (d, 1H,J=3.0 Hz), 4.86 (s, 1H), 4.43 (t, 2H, J=6.9 Hz), 4.22 (q, 2H, J=7.1 Hz),2.92 (t, 2H, J=6.9 Hz), 1.27 (t, 3H, J=7.1 Hz).

e). Ethyl 3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoate

A solution of the product of the preceding step (0.35 g, 1.51 mmol) andthe product of Example 1, Step b (0.24 g, 1.58 mmol) in anhydroustetrahydrofuran (25 mL) was treated with tri-n-butylphosphine (0.43 mL,1.72 mmol) and 1,1-(azodicarbonyl)dipiperidine (0.43 g, 1.70 mmol) atambient temperature. After 18 h the reaction was concentrated in vacuoand the crude product purified by flash column:chromatography (1:1methylene chloride:ethyl acetate eluant) giving the title compound as ayellow oil (0.33 g, 60%). ¹H NMR (400 MHz, CDCl₃) * 8.08 (dd, 1H, J=5Hz, 1 Hz), 7.40 (m, 1H), 7.24 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=3.1 Hz),7.09 (d, 1H, J=2.4 Hz), 6.89 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.55 (m, 1H),6.41 (d, 1H, J=8.4 Hz), 6.39 (d, 1H, J=3.0 Hz), 4.76 (br m, 1H), 4.45(t, 2H, J=6.9 Hz), 4.22 (q, 2H, J=7.1 Hz), 4.12 (m, 2H), 3.53 (dd, 2H,J=12.6 Hz, 6.5 Hz), 2.93 (t, 2H, J=6.9 Hz), 2.12 (pentet, 2H, J=6 Hz),1.27 (m, 3H).

f). 3-{5-[3-(2-Pyridylamino)propoxy]indolyl}propanoic acid ammonium salt

The product of the preceding step (0.33 g, 0.90 mmol) was dissolved inmethanol (10 mL) and treated with 1 N aqueous LiOH (2 mL) at ambienttemperature. After 18 h the reaction was acidified with 10% aqueous HCl,concentrated in vacuo, and the crude product purified by flash columnchromatography (15% methanol in methylene chloride eluant) giving a veryhygroscopic solid. This was dissolved in a mixture of methylene chlorideand methanol (saturated with ammonia gas), filtered, and the filtrateconcentrated in vacuo giving the title compound as a stable, pale yellowsolid (0.14 g, 42%). ¹H NMR (400 MHz, DMSO-d₆): * 7.92 (m, 1H), 7.59 (m,1H), 7.37 (d, 1H, J=8.9 Hz), 7.28 (d, 1H, J=3.1 Hz), 7.04 (d, 1H, J=2.3Hz), 6.78 (dd, 1H, J=8.9 Hz, 2.3 Hz), 6.75 (d, 1H, J=9.7 Hz), 6.63 (brt, 1H, J=6.3 Hz), 4.34 (t, 2H, J=6.8 Hz), 4.05 (t, 2H, J=6.2 Hz), 3.45(dd, 2H, J=12.5 Hz, 6.6 Hz), 2.71 (t, 2H, J=6.8 Hz), 2.02 (pentet, 2H,J=6.5 Hz). Mass spectrum (LCMS, ESI pos.) Calcd. for C₁₉H₂₁N₃O₃: 339.4(M+H). Found: 340.1.

EXAMPLE 2 3-{5-[3-(2-Pyridylamino)propoxy]indolyl}acetic acid ammoniumsalt

a). Methyl 2-(5-benzyloxyindolyl)acetate

5-Benzyloxyindole (0.80 g, 3.58 mmol) was dissolved in anhydrousN,N-dimethylformamide (20 mL) and treated with 60% sodium hydride inmineral oil (0.36 g, 9.00 mmol) at ambient temperature. After 2 h, ethylbromoacetate (0.45 mL, 4.06 mmol) was added, the reaction stirred for 6h, and additional sodium hydride (0.36 g, 9.00 mmol) was added. Thereaction stirred for 3 days, the N,N-dimethylformamide was removed invacuo, and the residue was dissolved in methylene chloride. Theresulting solution washed with 10% aqueous HCl, water, and brine, driedover anhydrous sodium sulfate, and filtered. The evaporated filtrate wasthen dissolved in N,N-dimethylformamide (20 mL) and treated with cesiumcarbonate (1.57 g, 4.80 mmol) and iodomethane (0.30 mL, 3.75 mmol) atambient temperature for 18 h. The reaction was concentrated in vacuo,the crude product dissolved in methylene chloride, and the solutionwashed with saturated aqueous bicarbonate, water, and brine, dried oversodium sulfate, and filtered. The evaporate filtrate then gave the titlecompound (0.93 g, 84%) as an oily orange solid. ¹H NMR (400 MHz,CDCl₃): * 7.46 (br d, 2H, J=7.3 Hz), 7.38 (m, 2H), 7.31 (d, 1H, J=7.2Hz), 7.17 (d, 1H, J=2.4 Hz), 7.14 (d, 1H, J=8.8 Hz), 7.06 (d, 1H, J=3.1Hz), 6.96 (dd, 1H, J=8.9 Hz, 2.4 Hz), 6.46 (d, 1H, J=3.1 Hz), 5.10 (s,2H), 4.79 (s, 2H), 4.20 (q, 2H, J=7.1 Hz), 1.25 (t, 3H, J=7.1 Hz).

b). Methyl 2-(5-hydroxyindolyl)acetate

A solution of the product of the preceding step (0.92 g, 2.97 mmol) and10% palladium(0) on carbon (94 mg) in reagent ethanol (40 mL) wasstirred under hydrogen at ambient pressure and temperature for 18 h. Thereaction was filtered over Celite, and the evaporated filtrate dissolvedin reagent ethanol (50 mL) and hydrogenated again as above over 10%palladium(0) on carbon (170 mg) for 24 h. The reaction was againfiltered over Celite, the evaporated filtrate dissolved in methylenechloride, poured over a short bed of silica gel, and eluted with 1:1methylene chloride:ethyl acetate. The eluate was then concentrated invacuo giving the title compound as a light brown oil (0.61 g, 93%). ¹HNMR (400 MHz, CDCl₃): * 7.09 (d, 1H, J=8.7 Hz), 7.06 (d, 1H, J=3.1 Hz),7.02 (d, 1H, J=2.4 Hz), 6.78 (dd, 1H, J=8.7 Hz, 2.4 Hz), 6.42 (m, 1H),4.79 (s, 2H), 4.21 (q, 2H, J=7.1 Hz), 1.25 (m, 3H).

c). Methyl 2-{5-[3-(2-pyridylamino)propoxy]indolyl}acetate

A solution of the product of the preceding step (0.31 g, 1.41 mmol) andthe product of Example 1, Step b (0.23 g, 1.48 mmol) in anhydroustetrahydrofuran (30 mL) was treated with tri-n-butylphosphine (0.41 mL,1.64 mmol) and 1,1-(azodicarbonyl)dipiperidine (0.41 g, 1.63 mmol) atambient temperature. After 18 h the reaction was concentrated in vacuoand the crude product purified by flash column:chromatography (1:1methylene chloride:ethyl acetate eluant) giving the title compound (0.24g, 48%) as a gold oil. ¹H NMR (400 MHz, CDCl₃): * 8.09 (m, 1H), 7.39(ddd, 1H, J=8.3 Hz, 7.2 Hz, 1.9 Hz), 7.13 (d, 1H, J=8.9 Hz), 7.10 (d,1H, J=2.3 Hz), 7.06 (d, 1H, J=3.1 Hz), 6.89 (dd, 1H, J=8.9 Hz, 2.3 Hz),6.55 (ddd, 1H, J=7.1 Hz, 5.1 Hz, 0.8 Hz), 6.46 (dd, 1H, J=3.1 Hz, 0.6Hz), 6.41 (d, 1H, J=8.4 Hz), 4.78 (m, 3H), 4.20 (q, 2H, J=7.1 Hz), 4.13(m, 2H), 3.52 (dd, 2H, J=12.6 Hz, 6.5 Hz), 2.12 (pentet, 2H, J=6.3 Hz),2.04 (s, 3H), 1.26 (m, 3H).

d). 2-{5-[3-(2-Pyridylamino)propoxy]indolyl}acetic acid ammonium salt

The product of the preceding step (0.23 g, 0.65 mmol) was dissolved inmethanol (15 mL) and treated with 1 N aqueous LiOH (2 mL) at ambienttemperature. After 3 days, the reaction was acidified with 10% aqueousHCl, concentrated in vacuo. The crude product purified by flash columnchromatography (25% methanol in methylene chloride saturated withammonia gas as eluant), the concentrated fractions treated with a fewdrops of 4 N HCl in dioxane, and concentrated in vacuo giving a yellowgum. This was dissolved in a mixture of methylene chloride and methanol(saturated with ammonia gas), filtered, and the filtrate concentrated invacuo giving the title compound as a yellow solid (0.16 g, 70%). ¹H NMR(400 MHz, DMSO-d₆): * 7.33 (m, 1H), 7.21 (d, 1H, J=2.9 Hz), 7.18 (d, 1H,J=8.8 Hz), 7.02 (d, 1H, J=2.2 Hz), 6.73 (dd, 1H, J=8.8 Hz, 2.1 Hz), 6.56(m, 1H), 6.45 (m, 2H), 6.26 (d, 1H, J=2.8 Hz), 4.65 (s, 2H), 4.03 (t,2H, J=6.3 Hz), 3.37 (m, 2H), 1.96 (m, 2H). Mass spectrum (LCMS, ESIpos.) Calcd. for C₁₈H₁₉N₃O₃: 326.4 (M+H). Found: 326.1.

EXAMPLE 3 3-{2-Methyl-5-[3-(2-pyridylamino)propoxy]indolyl}propanoicacid sodium salt

a). 3-(5-Methoxy-2-methylindolyl)propanoic acid

5-Methoxy-2-methylindole (0.50 g, 3.10 mmol) was dissolved in anhydrousN,N-dimethylformamide (25 mL) and treated with 60% sodium hydride inmineral oil (0.19 g, 4.70 mmol) at ambient temperature for 2 h. Ethyl3-bromopropionate (0.60 mL, 4.20 mmol) was added, the reaction stirredfor 3.5 h, treated with additional sodium hydride (0.20 g, 4.88 mmol),and stirred another 24 h. After concentration in vacuo, the crudeproduct was dissolved in methylene chloride, the solution washed withdilute aqueous HCl and brine, dried over anhydrous sodium sulfate, andfiltered. The evaporated filtrate was purified by flash columnchromatography (1:1 hexane:ethyl acetate as eluant) giving the titlecompound as a yellow-orange solid (0.56 g, 77%). ¹H NMR (400 MHz,CDCl₃): * 7.16 (d, 1H, J=8.8 Hz), 7.00 (d, 1H, J=2.4 Hz), 6.80 (dd, 1H,J=8.8 Hz, 2.4 Hz), 6.17 (s, 1H), 4.36 (t, 2H, J=7.4 Hz), 3.83 (s, 3H),2.78 (t, 2H, J=7.4 Hz), 2.41 (s, 3H).

b). 3-(5-Hydroxy-2-methylindolyl)propanoic acid

The product of the preceding step (0.55 g, 2.36 mmol) was dissolved inanhydrous methylene chloride (25 mL) under nitrogen, cooled to −78° C.,and treated with 1 N boron tribromide in methylene chloride (4.8 mL, 4.8mmol). The reaction was allowed to slowly warm to ambient temperatureover 18 h, quenched with excess water, and the phases separated. Theorganic phase washed with brine, dried over sodium sulfate, filtered,and the evaporated filtrate purified by flash column chromatography (10%methanol in methylene chloride as eluant) giving the title compound as alight brown oil (0.17 g, 32%). ¹H NMR (400 MHz, CDCl₃/CD₃OD): * 7.13 (d,1H, J=8.7 Hz), 6.92 (d, 1H, J=2.3 Hz), 6.71 (dd, 1H, J=8.7 Hz, 2.4 Hz),6.09 (s, 1H), 4.33 (t, 2H, J=7.5 Hz), 2.70 (t, 2H, J=7.5 Hz), 2.40 (s,3H).

c). Methyl 3-(5-hydroxy-2-methylindolyl)propanoate

A solution of the product of the preceding step (0.16 g, 0.73 mmol),sodium bicarbonate (0.06 g, 0.75 mmol), and iodomethane (0.06 mL, 0.96mmol) in N,N-dimethylformamide (10 mL) was stirred at ambienttemperature for 3 days. Additional sodium bicarbonate (0.10 g, 1.25mmol) and iodomethane (0.20 mL, 3.21 mmol) were added and the reactionstirred for another 24 h. The crude product was concentrated in vacuo,put onto a short bed of silica gel, eluted with 1:1 methylenechloride:ethyl acetate, and the eluate evaporated giving the titlecompound as a yellow oil (0.17 g, 97%). ¹H NMR (400 MHz, CDCl₃): * 7.12(d, 1H, J=8.7 Hz), 6.92 (d, 1H, J=2.4 Hz), 6.70 (dd, 1H, J=8.7 Hz, 2.5Hz), 6.12 (s, 1H), 4.53 (s, 1H), 4.35 (t, 2H, J=7.4 Hz), 3.67 (s, 3H),2.73 (t, 2H, J=7.4 Hz), 2.41 (m, 3H).

d). Methyl 3-{2-methyl-5-[3-(2-pyridylamino)propoxy]indolyl}propanoate

A solution of the product of the preceding step (0.16 g, 0.68 mmol) andthe product of Example 1, step b (0.12 g, 0.82 mmol) in anhydroustetrahydrofuran (15 mL) was treated with tri-n-butylphosphine (0.19 mL,0.76 mmol) and 1,1-(azodicarbonyl)dipiperidine (0.20 g, 0.79 mmol) atambient temperature. After 18 h the reaction was concentrated in vacuoand the crude product purified by flash column:chromatography (1:1methylene chloride:ethyl acetate eluant) giving the title compound as apale yellow solid (94 mg, 48%). ¹H NMR (400 MHz, CDCl₃): * 8.08 (dd, 1H,J=5.0 Hz, 1.1 Hz), 7.40 (m, 1H), 7.16 (d, 1H, J=8.8 Hz), 7.00 (d, 1H,J=2.4 Hz), 6.81 (t, 1H, J=8.8 Hz, 2.4 Hz), 6.55 (m, 1H), 6.41 (d, 1H,J=8.4 Hz), 6.15 (s, 1H), 4.76 (br s, 1H), 4.36 (t, 2H, J=7.4 Hz), 4.12(t, 2H, J=5.9 Hz), 3.67 (s, 3H), 3.52 (dd, 2H, J=12.6 Hz, 6.5 Hz), 2.73(t, 2H, J=7.4 Hz), 2.42 (s, 3H), 2.16 (pentet, 2H, J=6.2 Hz).

e). 3-{2-Methyl-5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acidsodium salt

The product of the preceding step (94 mg, 0.26 mmol) was dissolved inmethanol (10 mL) and treated with 1 N aqueous sodium hydroxide (1.5 mL)at ambient temperature for 18 h. The reaction was concentrated in vacuoand the crude product purified by preparative thin-layer chromatography(10% methanol in methylene chloride as eluant) giving the title compoundas pale yellow solid (34 mg, 35%). ¹H NMR (400 MHz, DMSO-d₆): * 7.95 (d,1H, J=4.3 Hz), 7.34 (m, 1H), 7.24 (d, 1H, J=8.8 Hz), 6.92 (d, 1H, J=2.2Hz), 6.68 (dd, 1H, J=8.6 Hz, 2.0 Hz), 6.54 (m, 1H), 6.44 (m, 2H), 6.06(s, 1H), 4.24 (br t, 2H, J=6.9 Hz), 4.01 (t, 2H, J=6.3 Hz), 3.38 (dd,2H, J=12.5 Hz, 6.5 Hz), 2.50 (m, 2H), 2.37 (s, 3H), 1.96 (pentet, 2H,J=6.5 Hz). Mass spectrum (LCMS, ESI pos.) Calcd. for C₂₀H₂₂N₃O₃: 354.4(M+H). Found: 354.2.

EXAMPLE 42-(trans-2-{5-[3-(2-Pyridylamino)propoxy]indolyl}cyclopropyl)acetic acid

a). Ethyl 2-bromocyclopropanecarboxylate

A mixture of vinyl bromide (50 g, 0.47 mol) and rhodium (II) acetatedimer (0.1 g, 0.2 mol) was dissolved in 20 ml of 1,2-dichloroethane.Ethyl diazoacetate (20 g, 0.18 mol) was added dropwise over a period of30 minutes. The reaction was stirred at room temperature for 4 h, thesolvent was removed under vacuum, and the residue was distilled with thehelp of an oil pump to obtain the title compound (14 g, 16%). ¹H NMR(400 MHz, CDCl₃) * 1.27 (t, 3H, J=7.1 Hz), 1.29 (m, 1H), 1.60 (m, 1H),2.04 (m, 1H), 3.23 (m, 1H), 4.21 (q, 2H, J=7.1 Hz).

b). Ethyl 2-(5-benzyloxyindolyl)cyclopropanecarboxylate

To a suspension of NaH (0.355 g, 14.0 mmol) in 100 ml of dryN,N-dimethylformamide was added slowly 5-benzyloxyindole (3.0 g, 13.4mmol). When the evolution of H₂ ceased, ethyl2-bromocyclopropanecarboxylate (2.85 g, 0.0148 mol), as prepared in thepreceding step, was added to the mixture and the reaction was refluxedfor a period of 17 h under argon. Then the reaction was cooled down atambient temperature and quenched carefully with water. After evaporationof the solvent under vacuum, the crude product was purified by flashchromatography on silica gel to obtain the title compound (3.45 g, 77%).¹H NMR (400 MHz, CDCl₃) * 1.34 (t, 3H, J=7.1 Hz), 1.62 (m, 1H), 1.73 (m,1H), 2.14 (m, 1H), 3.78 (m, 1H), 4.24 (c, 2H, J=7.1 Hz), 5.10 (s, 2H),6.36 (dd, 1H, J=0.7, 3.2 Hz), 6.98 (dd, 1H, J=2.4, 8.8 Hz), 7.04 (d, 1H,J=3.2 Hz), 7.14 (d, 1H, J=2.4 Hz), 7.38 (m, 4H), 7.45 (m, 2H).

c). Ethyl 2-(5-hydroxyindolyl)cyclopropanecarboxylate

Ethyl 2-(5-benzyloxyindolyl)cyclopropanecarboxylate (1.75 g, 0.0052mol), as prepared in the preceding step, was added under argon to asuspension of 10% of palladium(0) on carbon (0.50 g) in methanol (50mL). The reaction was carried out under H₂ atmosphere for a period of 6h. Filtration of the reaction over Celite and evaporation of thefiltrate yielded the title compound (1.27 g, 99%). ¹H NMR (400 MHz,CDCl₃) * 1.32 (t, 3H, J=7.1 Hz), 1.60 (m, 1H), 1.72 (m, 1H), 2.13 (m,1H), 3.77 (m, 1H), 4.25 (q, 2H, J=7.1 Hz), 6.29 (d, 1H, J=3.0 Hz), 6.81(d, 1H, J=8.3 Hz), 7.00 (m, 2H), 7.27 (m, 1H)

d). Ethyl2-{5-[3-(2-pyridylamino)propoxy]indolyl}cyclopropanecarboxylate

Ethyl 2-(5-hydroxyindolyl)cyclopropanecarboxylate (0.59 g, 2.40 mmol),as prepared in the preceding step, and 3-hydropropylaminopyridine (0.37g, 2.40 mmol), as prepared in step b of Example 1, were dissolved intetrahydrofuran (25 mL) at ambient temperature. tri-n-Butylphosphine(0.97 g, 4.80 mL) followed by 1,1=-(azodicarbonyl)dipiperidine (1.20 g,4.79 mmol) were added and the reaction was stirred at ambienttemperature overnight. The solvent was removed under vacuum and thecrude product was chromatographed on silica gel to obtain the titlecompound (0.38 g, 42%). ¹H-NMR (400 MHz, CDCl₃) * 1.34 (t, 3H, J=7.1Hz), 1.69 (m, 4H), 2.12 (m, 1H), 3.51 (m, 2H), 3.78 (m, 1H), 4.12 (t,2H, J=5.9 Hz), 4.26 (q, 2H, J=7.1 Hz), 4.80 (bs, 1H), 6.36 (dd, 1H,J=0.60, 3.1 Hz), 6.41 (d, 1H, J=8.4 Hz), 6.54 (m, 1H), 6.91 (dd, 1H,J=2.4, 8.8 Hz), 7.06 (dd, 1H, J=2.3, 9.2 Hz), 7.34 (d, 1H, J=8.8 Hz),7.39 (m, 1H), 8.07 (m, 1H). Mass spectrum (LCMS, ESI) Calcd. forC₂₁H₂₃N₃O₃: 366.2 (M+H); Found: 366.3.

e). 2-(trans-2-{5-[3-(2-pyridylamino)propoxy]indolyl}cyclopropyl)aceticacid

Ethyl 2-{5-[3-(2-pyridylamino)propoxy]indolyl}cyclopropane-carboxylate(0.38 g, 1.056 mmol), as prepared in the preceding step, was dissolvedin 7.5 mL of methanol. A solution of NaOH (0.13 g, 3.18 mmol) in water(2.5 mL) was added and the reaction was stirred at ambient temperatureovernight. The base was then neutralized with an aqueous solution of HCl(3.18 mmol), and the solvent was evaporated under vacuum. The crudeproduct was chromatographed on silica gel to obtain the title compound(200 mg, 57%). ¹H NMR (400 MHz, CDCl₃) * 1.66 (m, 2H), 2.00 (m, 1H),2.16 (m, 2H), 3.58 (m, 2H), 3.72 (m, 1H), 4.12 (t, 2H, J=5.8 Hz), 6.31(dd, 1H, J=0.7, 3.2 Hz), 6.77 (m, 1H,), 6.85 (dd, 1H, J=2.3, 8.8 Hz),6.97 (d, 1H, J=9.0 Hz), 7.06 (d, 1H, J=2.3 Hz), 7.13 (d, 1H, J=3.2 Hz),7.33 (d, 1H, J=8.8 Hz), 7.77 (m, 2H). Mass spectrum (LCMS, ESI pos.)Calcd. for C₂₁H₂₃N₃O₃ 352.2 (M+H);

Found: 352.2.

EXAMPLE 5 3-(5-{2-[6-(Methylamino)-2-pyridyl]ethoxy}indolyl)propanoicacid

a). (tert-Butoxy)-N-[6-methyl-(2-pyridyl)]carboxamide

A mixture of 2-amino-picoline (6.0 g, 5.5 mmol) anddi-tert-butyldicarbonate (13.3 g, 6.0 mmol) was heated to 60□C overnight(16 h). The reaction was cooled and poured into saturated NH₄Cl (250 mL)and extracted ethyl acetate (2×250 mL). The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated to give ayellow oil (crude 12.3 g) which was used directly in the next reaction.

b). (tert-Butoxy)-N-methyl-N-[6-methyl-(2-pyridyl)]carboxamide

To a suspension of NaH (2.63 g 6.6 mmol) in 200 mL ofN,N-dimethylformamide at 0□C was added a solution of(tert-butoxy)-N-[6-methyl-(2-pyridyl)]carboxamide (12.3 g, crude), asprepared in the preceding step, in 50 mL of N,N-dimethylformamide. Thereaction stirred at 0□C for 15 min then at ambient temperature for 1 h.Then iodomethane (10.22 g, 7.2 mmol) was added and the mixture wasstirred at ambient temperature overnight (16 h). The reaction mixturewas concentrated in vacuo, diluted with saturated NH₄Cl (400 mL), andextracted with ethyl acetate (2×250 mL). The combined organic layerswere washed with brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by flash chromatography on silica gel (10% ethylacetate in hexane) to give the title compound as a yellow oil (7.56 g,57%). ¹H-NMR (400 MHz, DMSO-d₆) * 7.63 (t, J=7.2 Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 6.97 (d, J=6.9 Hz, 1H), 3.27 (s, 2H), 2.42 (s, 3H), 1.45 (s,9H).

c). Ethyl 2-{6-[(tert-butoxy)-N-methylcarbonylamino]-2-pyridyl}acetate

Lithium diisopropylamide (6.6 mmol) was prepared in tetrahydrofuran (60mL), cooled to −78□C, and(tert-butoxy)-N-methyl-N-[6-methyl-(2-pyridyl)]carboxamide (7.56 g, 3.3mmol), as prepared in the preceding step, was dissolved intetrahydrofuran (100 mL) and added dropwise over 30 min. The mixture wasstirred for 15 min then diethylcarbonate (6.24 g, 5.3 mmol) was added.The solution was stirred for an additional 15 min, then allowed to warmto 0□C over 2 h. The reaction was quenched with saturated NH₄Cl solution(200 mL). The mixture was allowed to warm to ambient temperature andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by flash chromatography (silica gel, 10% ethylacetate in hexane) to give the title compound as a yellow oil (5.51 g,60%). ¹H-NMR (400 M Hz, DMSO-d₆) δ 7.71 (t, J=7.9 Hz, 1H), 7.49 (d,J=8.2 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.78 (s,2H), 2.54 (s, 3H), 1.46 (s, 9H), 1.18 (t, J=7.1 Hz, 3H).

d). Ethyl 2-[6-(methylamino)-2-pyridylacetate

A solution of ethyl2-{6-[(tert-butoxy)-N-methylcarbonylamino]-2-pyridyl}acetate (5.51 g,1.9 mmol), as prepared in the preceding step, in methylene chloride (25mL) was stirred in an ice bath at 0□C. Trifluoroacetic acid (10 mL) wasthen added and the solution were allowed to warm to ambient temperatureand stirred overnight (16 h). The reaction mixture was concentrated, 10%aqueous K₂CO₃ (300 mL) was added and the mixture was extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered and concentrated to give the titlecompound as a bright yellow oil (3.4 g, 100%). ¹H-NMR (400 MHz, DMSO-d₆)δ 7.32 (t, J=7.2 Hz, 1H), 6.40 (d, J=7.0 Hz, 1H), 6.29 (d, J=8.3 Hz,1H), 4.07 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.71 (d, J=4.9 Hz, 3H), 1.17(t, J=7.1 Hz, 3H).

e). 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol

To a suspension of lithium aluminum hydride (1.8 g, 4.9 mmol) intetrahydrofuran (50 mL) was added dropwise a solution of ethyl2-[6-(methylamino)-2-pyridylacetate (3.5 g, 1.9 mmol), as prepared inthe preceding step, in tetrahydrofuran (50 mL) at 0□C. After theaddition was completed, the reaction mixture was stirred at 0□C for 30minutes then stirred at ambient temperature for 2 h. The reactionmixture was then cooled back to 0□C and quenched with H₂O (1.8 mL), 10%NaOH (1.8 mL) and H₂O (3.0 mL) and allowed to warm back to ambienttemperature. The solids were removed by filtration through Celite andwashed with tetrahydrofuran (100 mL). The filtrate was dried (Na₂SO₄),filtered and concentrated. The residue was purified by flashchromatography on silica gel (3% methanol in methylene chloride) to givethe title compound as a yellow oil (2.1 g, 70%). ¹H-NMR (400 MHz, CDCl₃)δ 7.36 (t, J=7.8 Hz, 1H), 6.41 (d, J=7.2 Hz, 1H), 6.26 (d, J=8.3 Hz,1H), 4.51 (br s, 1H), 3.96 (t, J=5.2 Hz, 2H), 2.89 (d, J=5.1 Hz, 3H),2.84 (t, J=5.4 Hz, 2H).

f). Methyl 3-(5-benzyloxyindolyl)propanoate

To a solution of 5-benzyloxyindole (1.15 g, 5 mmol) inN,N-dimethylformamide (40 mL) was added sodium hydride (200 mg, 5 mmol).After stirring for 30 minutes, ethyl bromopropionate (900 mg, 5.0 mmol)was added and the mixture was stirred at ambient temperature for 1 h,additional sodium hydride (100 mg, 2.5 mmol) was added. After stirringfor 10 minutes, additional ethyl bromopropionate (180 mg, 1.0 mmol) wasadded. The mixture was stirred at ambient temperature overnight. Thesolvent was removed under high vacuum, the residue was dissolved inwater (10 mL) and tetrahydrofuran (10 mL), NaOH (500 mg) was added andstirred for 2 h. After acidifying to pH 4-5, the mixture was extractedwith methylene chloride. The methylene chloride layer washed with brineand dried over Na₂SO₄. After evaporating the solvent in vacuo, theresidue was purified by flash column chromatography (1-5% ethyl acetatein methylene chloride) to give 3-(5-benzyloxyindolyl)propanic acid aswhite solid. The solid was dissolved in N,N-dimethylformamide (20 mL),K₂CO₃ (110 g) and iodomethane (840 mg) were added and the reaction wasstirred at ambient temperature for 3 h. The mixture was concentratedunder high vacuum and residue was purified by flash columnchromatography (methylene chloride) to give the title compound as acolorless oil (1.10 g, 71%). ¹H-NMR (400 MHz, CDCl₃) δ 7.47 (d, J=7.3Hz, 2H), 7.38 (t, J=7.3 Hz, 2H), 7.32 (d, J=7.2 Hz, 1H), 7.23 (d, J=10.2Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 6.96 (dd,J=8.8, 2.5 Hz, 1H), 6.39 (d, J=3.1 Hz, 1H), 5.10 (s, 2H), 4.41 (t, J=6.9Hz, 2H), 3.66 (s, 3H), 2.81 (t, J=6.8 Hz, 2H).

g). Methyl 3-(5-hydroxyindolyl)propanoate

A mixture of methyl 3-(5-benzyloxyindolyl)propanoate (1.1 g, 3.56 mmol),as prepared in the preceding step, 10% palladium(0) on carbon (100 mg)in ethanol was stirred under hydrogen for 3 h. The catalyst was removedby filtration, the filtrate was concentrated in vacuo and the residuewas purified by flash column chromatography (1-5% ethyl acetate inmethylene chloride) to give the title compound as a pale yellow oil (700mg, 90%). ¹H-NMR (400 M Hz, CDCl₃) δ 7.18 (d, J=8.8 Hz, 1H), 7.08 (d,J=3.1 Hz, 1H), 7.02 (d, J=3.2 Hz, 1H), 6.77 (dd, J=8.8, 2.5 Hz, 1H),6.34 (d, J=3.1 Hz, 1H), 4.75 (s, 1H), 4.40 (t, J=6.9 Hz, 2H), 3.66 (s,3H), 2.81 (t, J=6.9 Hz, 2H).

h). Methyl 3-(5-{2-[6-(methylamino)-2-pyridyl]ethoxy}indolyl)propanoate

Diisopropyl azodicarboxylate (0.19 g, 0.94 mmol) was added to a solutionof 2-[6-(methylamino)-2-pyridyl]ethan-1-ol (0.10 g, 0.66 mmol), asprepared in step e of Example 5, methyl 3-(5-hydroxyindolyl)propanoate(0.10 g, 0.46 mmol), as prepared in the preceding step, andtriphenylphosphine (0.24 g, 0.92 mmol) in tetrahydrofuran (5.0 mL) at0□C in an ice bath. After stirring at ambient temperature overnight (16h), the reaction was concentrated and the residue was purified by flashchromatography on silica gel (20%-30% ethyl acetate in hexane) to givethe title compound as a yellow oil (0.023 g, 15%). ¹H-NMR (400 M Hz,CDCl₃) δ 7.39 (t, J=7.3 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.11 (d, J=2.3Hz, 1H), 7.07 (d, J=3.1 Hz, 1H), 6.87 (dd, J=2.4, 8.9 Hz, 1H), 6.56 (d,J=7.2 Hz, 1H), 6.37 (d, J=3.1 Hz, 1H), 6.24 (d, J=8.2 Hz, 1H), 4.56 (brs, 1H), 3.40 (t, J=6.9 Hz, 2H), 4.34 (t, J=7.0 Hz, 2H), 3.65 (s, 3H),3.10 (t, J=7.0 Hz, 2H), 2.89 (d, J=4.8 Hz, 2H), 2.80 (t, J=6.9 Hz, 2H).

i). 3-(5-{2-[6-(methylamino)-2-pyridyl]ethoxy}indolyl)propanoic acid

To a solution of methyl3-(5-{2-[6-(methylamino)-2-pyridyl]ethoxy}indolyl)propanoate (0.023 g,0.65 mmol), as prepared in the preceding step, in methanol (3 mL) wasadded sodium hydroxide (0.15 g, 3.8 mmol) in H₂O (0.5 mL) and thereaction was stirred for 6 hours at ambient temperature. Afterevaporating the solvent in vacuo, the residue is taken up in H₂O (5 mL)and acidified to pH 4-5 with 10% HCl, extracted with a mixture of ethylacetate and butanol (2×50 mL) and the combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated to give thetitle compound as a solid (0.018 g, 82%). ¹H-NMR (400 M Hz, CDCl₃+CD₃OD)δ 7.52 (t, J=7.3 Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 7.14 (d, J=3.1 Hz,1H), 7.06 (d, J=2.3 Hz, 1H), 6.81 (dd, J=8.9, 2.4 Hz, 1H), 6.60 (d,J=7.3 Hz, 1H), 6.38 (d, J=8.6 Hz, 1H), 6.33 (d, J=3.2 Hz, 1H), 4.38 (t,J=7.0 Hz, 2H), 4.24 (t, J=6.6 Hz, 2H), 3.06 (t, J=6.6 Hz, 2H), 2.89 (s,3H), 2.77 (t, J=6.9 Hz, 2H). Mass spectrum (LCMS, ESI pos.) Calcd. forC₁₉H₂₁N₃O₃ 340.3 (M+H); Found: 340.9.

EXAMPLE 6 2-Benzyl-3-{5 [3-(2-pyridylamino)propoxy]indolyl}propanoicacid

a). Methyl 3-[5-(benzyloxyindolyl]-2-benzylpropanoate

Lithium diisopropylamide (0.55 mmol) was prepared in tetrahydrofuran(4.0 mL), cooled to −78□C, and treated with a solution of methyl3-(5-benzyloxyindolyl)propanoate (0.15 g, 0.49 mmol), as prepared in thestep f of Example 5, in tetrahydrofuran (4.0 mL). After stirring for 90min at −78_C, benzyl bromide (0.08 g, 0.49 mmol) was added and thereaction mixture was allowed to warm to ambient temperature slowly over3 h. The reaction mixture was poured into saturated NH₄Cl (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by flash chromatography on silica gel (8% ethylacetate in hexane) to give the title compound as an oil (0.09 g, 50%).¹H-NMR (400 MHz, CDCl₃) δ 7.46 (d, J=7.2 Hz, 2H), 7.30 (m, 4H), 7.26 (m,1H), 7.16 (m, 3H), 7.00 (m, 2H), 6.88 (dd, J=2.4, 8.6 Hz, 1H), 6.36 (m,1H), 5.08 (s, 2H), 4.40 (dd, J=8.9, 13.9 Hz, 1H), 4.15 (dd, J=14.4, 5.3Hz, 1H), 3.50 (s, 3H), 3.23, (m, 1H), 3.04 (dd, J=13.1, 7.8 Hz, 1H),2.76 (dd, J=14.4, 7.1 Hz, 1H).

b). Methyl 3-(5-hydroxylindolyl)-2-benzylpropanoate

A mixture of methyl 3-(5-benzyloxyindolyl)-2-benzylpropanoate (0.16,0.39 mmol), as prepared in the preceding step, 10% palladium(0) oncarbon (0.02 g) in ethanol (10 mL) was stirred at ambient temperatureunder hydrogen (balloon) overnight (16 h). The catalyst was removed byfiltration through Celite. The filtrate was concentrated to give thetitle compound as a light brown oil (0.12 g, 100%) which was useddirectly in next reaction.

c). Methyl 2-benzyl-3-{5-[2-(pyridylamino)propoxy]indolyl}propanoate

1,1′-(Azodicarbonyl)dipiperidine (0.18 g, 0.7 mmol) was added to asolution of methyl 3-(5-hydroxylindolyl)-2-benzylpropanoate (0.12 g,0.39 mmol), as prepared in the preceding step,2-(3-hydroxypropyl)aminopyridine (0.07 g, 0.47 mmol), as prepared instep b of Example 1, and tri-n-butylphosphine (0.14 g, 0.7 mmol) intetrahydrofuran (6.0 mL). After stirring at ambient temperatureovernight (16 h), the reaction was concentrated in vacuo and the residuepurified by flash chromatography on silica gel (10%-50% ethyl acetate inhexane) to give the title compound as a yellow oil (0.064 g, 38%).¹H-NMR (400 MHz, CDCl₃) δ 8.08 (br s, 1H), 7.40 (m, 1H), 7.37 (m, 1H),7.22 (m, 2H), 7.00 (m, 3H), 6.84 (dd, J=8.9, 2.4 Hz, 1H), 6.54 (m, 1H),6.40 (d, J=8.4 Hz, 2H), 6.36 (d, J=3.1 Hz, 1H), 4.77 (br s, 1H), 4.40(m, 1H), 4.17 (m, 3H), 3.52 (m, 5H), 3.24 (m, 1H), 3.08 (m, 1H), 2.76(m, 1H), 2.11 (m, 2H).

d). 2-Benzyl-3-{5 [3-(2-pyridylamino)propoxy]indolyl}propanoic acid

To a solution of methyl2-benzyl-3-{5-[2-(pyridylamino)propoxy]indolyl}propanoate (0.06 g, 0.13mmol), as prepared in the preceding step, in methanol (3.0 mL) was addeda solution of NaOH (0.1 g, 2.5 mmol) in H₂O (0.3 mL), and the reactionwas stirred at ambient temperature overnight. After evaporating thesolvent in vacuo, the residue is mixed with H₂O (5 mL) and acidified topH 4-5 with 10% HCl, extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated. The residue was purified by flash chromatography onsilica gel (4% methanol in methylene chloride) to give the titlecompound as an oil (0.043 g, 80%). ¹H-NMR (400 MHz, CDCl₃) δ 7.66 (d,J=4.7 Hz, 1H), 7.50 (m, 1H), 7.22 (m, 3H), 7.11 (d, J=8.9 Hz, 1H), 7.04(d, J=2.8 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.71 (dd, J=8.8, 2.3 Hz, 1H),6.50 (m, 2H), 6.24 (d, J=2.7 Hz, 1H), 4.32 (m, 1H), 4.0 (m, 1H), 3.91(t, J=5.7 Hz, 2H), 3.28 (t, J=6.6 Hz, 2H), 3.15 (m, 1H), 2.75 (m, 1H),1.93 (m, 2H). Mass spectrum (LCMS, ESI pos.) Calcd. for C₂₆H₂₇N₃O₃ 430.5(M+H); Found: 430.2.

EXAMPLE 7 2-Methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoicacid

a). Methyl 2-methyl-3-(5-benzyloxyindolyl)propanoate

Lithium diisopropylamide (0.99 mmol) was prepared in tetrahydrofuran(4.0 mL), cooled to −78□C, and methyl 3-(5-benzyloxyindolyl)propanoate(0.19 g, 0.62 mmol), as prepared in step f of Example 5, was addeddropwise in tetrahydrofuran (4.0 mL). After stirring for 90 min at−78□C, iodomethane (0.44 g, 3.1 mmol) was added and the reaction wasallowed to warm to ambient temperature slowly over 3 h. The reactionmixture was poured into saturated NH₄Cl (20 mL) and extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brine,dried (Na₂SO₄), filtered and concentrated. The residue was purified byflash chromatography on silica gel (8% ethyl acetate in hexane) to givethe title compound as an oil (0.18 g, 90%). ¹H-NMR (400 MHz, CDCl₃) δ7.47 (d, J=6.9 Hz, 2H), 7.39 (m, 2H), 7.33 (m, 1H), 7.24 (d, J=8.9 Hz,1H), 7.15 (d, J=2.4 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 6.95 (dd, J=8.9,2.5 Hz, 1H), 6.38 (d, J=3.2 Hz, 1H), 5.10 (s, 2H), 4.42 (dd, J=14.4, 7.3Hz, 1H), 4.08 (dd, J=14.4, 7.1 Hz, 1H), 3.63 (s, 3H), 3.01 (q, J=7.1 Hz,1H), 1.16 (d, J=7.1 Hz, 3H).

b). Methyl 3-(5-hydroxyindolyl)-2-methylpropanoate

A mixture of methyl 2-methyl-3-[5-benzyloxyindolyl]propanoate (0.18 g,0.56 mmol), as prepared in the preceding step, 10% palladium(0) oncarbon (0.018 g) in ethanol (10 mL) was stirred at ambient temperatureunder hydrogen (balloon) overnight (16 h). The catalyst was removed byfiltration through Celite. The filtrate was concentrated to give thetitle compound as a light brown oil (0.11 g, 85%) which was useddirectly in the next reaction.

c). Methyl 2-methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoate

1,1′-(Azodicarbonyl)dipiperidine (0.13 g, 0.57 mmol) was added to thesolution of methyl 3-(5-hydroxyindolyl)-2-methylpropanoate (0.062 g,0.27 mmol), as prepared in the preceding step,2-(3-hydroxypropyl)aminopyridine (0.06 g, 0.40 mmol), as prepared instep b of Example 1, and tri-n-butylphosphine (0.11 g, 0.53 mmol) intetrahydrofuran (6.0 mL). After stirring at ambient temperatureovernight (16 h), the reaction was concentrated and the residue waspurified by flash chromatography on silica gel (10%-50% ethyl acetate inhexane) to give the title compound as a yellow oil (0.015 g, 15%).¹H-NMR (400 MHz, CDCl₃) δ 8.07 (m, 1H), 7.40 (m, 1H), 7.21 (d, J=8.9 Hz,1H), 7.08 (d, J=2.4 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 6.88 (dd, J=8.9,2.4 Hz, 1H), 6.54 (m, 1H), 6.41 (m, 1H), 4.89 (br s, 1H), 4.45 (dd,J=14.2, 7.3 Hz, 1H), 4.10 (m, 4H), 3.63 (s, 3H), 5.52 (q, J=6.5 Hz, 2H),2.13 (m, 2H), 1.66 (m, 1H), 1.52 (m, 1H), 1.16 (d, J=7.1 Hz, 3H), 0.93(m, 3H).

d). 2-methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid

To a solution of methyl2-methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoate (0.015 g,0.04 mmol), as prepared in the preceding step, in methanol (5.0 mL) wasadded a solution of NaOH (0.1 g, 2.5 mmol) in H₂O (0.3 mL), and thereaction was stirred at ambient temperature overnight. After evaporatingthe solvent in vacuo, the residue is taken up in H₂O (5 mL) andacidified to pH 4-5 with 10% HCl and extracted with ethyl acetate (2×15mL). The combined organic layers were washed with brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by flashchromatography on silica gel (4% methanol in methylene chloride) to givethe title compound as an oil (0.011 g, 80%). ¹H-NMR (400 MHz, CDCl₃) δ7.86 (d, J=5.6 Hz, 1H), 7.50 (m, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.07 (dd,J=13.1, 2.8 Hz, 2H), 6.84 (dd, J=8.9, 2.4 Hz, 1H), 6.56 (m, 2H), 6.32(d, J=2.0 Hz, 1H), 4.38 (dd, J=14.3, 7.0 Hz, 1H), 4.07 (t, J=5.8 Hz,2H), 4.01 (dd, J=14.3, 7.5 Hz, 1H), 3.44 (t, J=6.7 Hz, 2H), 2.92 (q,J=7.1 Hz, 1H), 2.08 (m, 2H), 1.12 (d, J=7.1 Hz, 3H). Mass spectrum(LCMS, ESI pos.) Calcd. for C₂₀H₂₃N₃O₃ 354.3 (M+H); Found: 354.2.

EXAMPLE 8 2-({5-[3-(2-Pyridylamino)propoxy]indolyl}methyl)pentanoic acid

a). Methyl 2-[(5-benzyloxyindolyl)methyl]pentanoate

Lithium diisopropylamide (0.51 mmol) was prepared in tetrahydrofuran(4.0 mL), cooled to −78□C, and methyl 3-(5-benzyloxyindolyl)propanoate(0.14 g, 0.46 mmol), as prepared in step f of Example 5, was addeddropwise in tetrahydrofuran (4.0 mL). After stirring for 90 min at−78□C, iodopropane (0.08 g, 0.46 mmol) was added and the reactionmixture was allowed to warm to ambient temperature slowly over 3 h. Thereaction mixture was poured into saturated NH₄Cl (20 mL) and extractedwith ethyl acetate (2×50 mL). The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography on silica gel (8% ethyl acetate inhexane) to give the title compound as an oil (0.025 g, 16%). ¹H-NMR (400MHz, CDCl₃) δ 7.47 (m, 2H), 7.39 (m, 2H), 7.31 (m, 1H), 7.21 (d, J=8.9Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.02 (d, J=3.1 Hz, 1H), 6.95 (dd,J=8.9, 2.4 Hz, 1H), 6.37 (dd, J=3.1, 0.7 Hz, 1H), 5.10 (s, 2H), 4.37(dd, J=14.4, 8.5 Hz, 1H), 4.15 (dd, J=14.4, 6.1 Hz, 1H), 3.57 (s, 3H),2.95 (m, 1H), 1.64 (m, 1H), 1.42 (m, 3H), 0.90 (t, J=7.3 Hz, 3H).

b). Methyl 2-[(5-hydroxyoxyindolyl)methylpentanoate

A mixture of methyl 2-[(5-benzyloxyindolyl)methyl]pentanoate (0.036 g),as prepared in the preceding step, 10% palladium(0) on carbon (0.005 g)in ethanol (5 mL) was stirred at ambient temperature under hydrogen(balloon) overnight (16 h). The catalyst was removed by filtrationthrough Celite. The filtrate was concentrated to give the title compoundas a light brown oil (0.03 g, 100%) which was used directly in the nextreaction.

c). Methyl 2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)pentanoate

1,1′-(Azodicarbonyl)dipiperidine (0.12 g, 0.48 mmol) was added to thesolution of methyl 2-[(5-hydroxyindolyl)methyl]pentanoate (0.03 g, 0.12mmol), as prepared in the preceding step,2-(3-hydroxypropyl)aminopyridine (0.026 g, 0.17 mmol), as prepared instep b of Example 1, and tri-n-butylphosphine (0.09 g, 0.46 mmol) intetrahydrofuran (6.0 mL). After stirring at ambient temperatureovernight (16 h), the reaction was concentrated and the residue waspurified by flash chromatography on silica gel (10%-50% ethyl acetate inhexane) to give the title compound as a yellow oil (0.016 g, 36%).¹H-NMR (400 MHz, CDCl₃) δ 8.08 (m, 1H), 7.39 (m, 1H), 7.20 (d, J=8.9 Hz,1H), 7.07 (d, J=2.4 Hz, 1H), 7.02 (d, J=3.3 Hz, 1H), 6.88 (dd, J=8.9,2.4 Hz, 1H), 6.53 (m, 1H), 6.40 (m, 2H), 4.32 (br s, 1H), 4.42 (m, 1H),4.25 (m, 3H), 3.52 (m, 5H), 2.91 (m, 1H), 2.20 (m, 2H), 1.72 (m, 2H),1.43 (m, 3H), 0.95 (t, J=7.2 Hz, 3H).

d). 2-({5-[3-(2-Pyridylamino)propoxy]indolyl}methyl)pentanoic acid

To a solution of methyl2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)pentanoate (0.015 g,0.004 mmol), as prepared in the preceding step, in methanol (2.0 mL) wasadded a solution of NaOH (0.1 g, 2.5 mmol) in H₂O (0.3 mL), and thereaction was stirred at ambient temperature overnight. After evaporatingthe solvent in vacuo, the residue is taken up in H₂O (5 mL) andacidified to pH 4-5 with 10% HCl, and extracted with ethyl acetate (2×15mL). The combined organic layers were washed with brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by flashchromatography on silica gel (4% methanol in methylene chloride) to givethe title compound as an oil (0.011 g, 85%). ¹H-NMR (400 MHz, CDCl₃) δ8.28 (br s, 1H), 7.72 (d, J=4.5 Hz, 1H), 7.49 (m, 1H), 7.26 (d, J=8.9Hz, 1H), 7.06 (d, J=3.0 Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 6.78 (dd,J=8.9, 2.4 Hz, 1H), 6.5 (m, 2H), 6.27 (d, J=2.8 Hz, 1H), 4.25 (dd,J=14.1, 8.4 Hz, 1H), 3.97 (m, 3H), 3.33 (t, J=6.6 Hz, 2H), 2.87 (br s,1H), 1.96 (m, 2H), 1.67 (m, 1H), 1.45 (m, 3H), 0.90 (t, J=6.8 Hz, 3H).Mass spectrum (LCMS, ESI pos.) Calcd. for C₂₂H₂₇N₃O₃ 382.5 (M+H); Found:382.2.

EXAMPLE 9 2-({5-[3-(2-Pyridylamino)propoxy]indolyl}methyl)octanoic acid

a) Methyl 2-[(5-benzylindolyl)methyloctanoate

Lithium diisopropylamide (1.3 mmol) was prepared in tetrahydrofuran (4.0mL), cooled to −78□C, and a solution of methyl3-(5-benzyloxyindolyl)propanoate (0.21 g, 0.7 mmol), as prepared in stepf of Example 5, was added dropwise in tetrahydrofuran (4.0 mL). Afterstirring for 90 min at −78□C, iodohexane (0.7 g, 3.4 mmol) was added andthe reaction mixture was allowed to warm to ambient temperature over 3h. The reaction mixture was poured into saturated NH₄Cl (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by flash chromatography on silica gel (8% ethylacetate in hexane) to give the title compound as an oil (0.13 g, 50%).¹H-NMR (400 MHz, CDCl₃) _(—) 7.47 (d, J=7.0 Hz, 1H), 7.37 (m, 2H), 7.32(m, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.02 (d, J=3.1Hz, 1H), 6.95 (dd, J=8.9, 2.5 Hz, 1H), 6.37 (d, J=3.1 Hz, 1H), 5.09 (s,2H), 4.35 (dd, J=14.4, 8.5 Hz, 1H), 4.13 (dd, J=14.4, 6.1 Hz, 1H), 3.57(s, 3H), 2.91 (m, 1H), 1.64 (m, 1H), 1.48 (m, 1H), 1.30 (m, 6H), 0.87(t, J=6.9 Hz, 3H).

b) Methyl 2-[(5-hydroxyindolyl)methyloctanoate

A mixture of methyl 2-[(5-benzyloxyindolyl)methyloctanoate (0.15 g, 0.37mmol), as prepared in the preceding step, 10% palladium(0) on carbon inethanol (10 mL) was stirred at ambient temperature under hydrogen(balloon) overnight (16 h). The catalyst was removed by filtrationthrough Celite. The filtrate was concentrated to give the title compoundas a light brown oil (0.11 g, 100%) which was used directly in the nextreaction.

c) Methyl 2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)octanoate

1,1′-(Azodicarbonyl)dipiperidine (0.19 g, 0.75 mmol) was added to thesolution of methyl 2-[(5-hydroxyindolyl)methyloctanoate (0.11 g, 0.38mmol), as prepared in the preceding step,2-(3-hydroxypropyl)aminopyridine (0.09 g, 0.56 mmol), as prepared instep b of Example 1, and tri-n-butylphosphine (0.13 g, 0.75 mmol) intetrahydrofuran (6.0 mL). After stirring at ambient temperatureovernight (16 h), the reaction was concentrated and the residue waspurified by flash chromatography on silica gel (10%-50% ethyl acetate inhexane) to give the title compound as a yellow oil (0.04 g, 25%). ¹H-NMR(400 MHz, CDCl₃) δ 8.80 (m, 1H), 7.40 (m, 1H), 7.21 (d, J=9.0 Hz, 1H),7.08 (d, J=2.3 Hz, 1H), 7.03 (d, J=3.1 Hz, 1H), 6.88 (dd, J=9.2, 2.4 Hz,1H), 6.55 (m, 2H), 6.40 (m, 2H), 4.81 (br s, 1H), 4.37 (dd, J=14.4, 8.5Hz, 1H), 4.14 (m, 3H), 3.69 (s, 3H), 3.65 (m, 2H), 2.94 (m, 1H), 2.15(m, 2H), 1.50 (m, 7H), 0.90 (m, 3H).

d) 2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)octanoic acid

To a solution of methyl2-({5-[3-(2-pyridylamino)propoxy]-indolyl}methyl)octanoate (0.04 g, 0.09mmol), as prepared in the preceding step, in methanol (5.0 mL) was addeda solution of NaOH (0.1 g, 2.5 mmol) in H₂O (0.3 mL), and the reactionwas stirred at ambient temperature overnight. After evaporating thesolvent in vacuo, the residue is taken up in H₂O (5 mL) and acidified topH 4-5 with 10% HCl, and extracted with ethyl acetate (2×15 mL). Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated. The residue was purified by flash chromatography onsilica gel (4% methanol in methylene chloride) to give the titlecompound as an oil (0.34 g, 90%). ¹H-NMR (400 MHz, CDCl₃) δ 7.72 (m,1H), 7.48 (m, 1H), 7.26 (d, 8.9 Hz, 1H), 7.02 (d, J=2.7 Hz, 2H), 6.77(dd, J=8.9, 2.4 Hz, 1H), 6.50 (m, 2H), 6.28 (d, J=2.9 Hz, 1H), 4.27 (dd,J=14.2, 8.6 Hz, 1H), 3.99 (m, 3H), 3.32 (t, J=6.7 Hz, 2H), 2.85 (br s,1H), 1.95 (m, 2H), 1.67 (m, 1H), 1.30 (m, 9H), 0.84 (t, J=6.6 Hz, 3H).Mass spectrum (LCMS, ESI pos.) Calcd. for C₂₅H₃₃N₃O₃ 424.2 (M+H); Found:424.7.

EXAMPLE 10 3-[5-(3-{[Benzylamino]carbonylamino}propoxy)indolyl]propanoicacid

a) Methyl 3-{5-[3-(benzyloxycarbonylamino)propoxy]indolyl}propanoate

1,1=-(Azodicarbonyl)dipiperidine (370 mg, 1.5 mmol) was added to thesolution of methyl 3-(5-hydroxyindolyl)propanoate (220 mg, 1.0 mmol), asprepared in step g of Example 5,3-(benzyloxycarbonylamino)propanol (230mg, 1.1 mmol) and tri-n-butylphosphine (305 mg, 1.5 mmol) intetrahydrofuran (20 mL). After stirring at ambient temperatureovernight, the reaction mixture was concentrated and the residue waspurified by flash column chromatography on silica gel (0-2% ethylacetate in methylene chloride) to give the title compound as an offwhite solid (310 mg, 76%). ¹H-NMR (400 MHz, CDCl₃) δ 7.35 (m, 5H), 7.22(d, J=8.9 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 7.07 (d, J=2.1 Hz, 1H), 6.86(dd, J=8.8, 2.4 Hz, 1H), 6.38 (d, J=2.9 Hz, 1H), 5.11 (br s, 3H), 4.41(t, J=6.8 Hz, 2H), 4.07 (t, J=5.9 Hz, 2H), 3.66 (s, 3H), 3.44 (q, J=6.3Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 2.02 (m, 2H).

b) Methyl 3-[5-(aminopropoxy)indolyl]propanoate

A mixture of methyl3-{5-[3-(benzyloxycarbonylamino)propoxy]-indolyl}propanoate (300 mg,0.73 mmol), as prepared in the preceding step, 10% palladium(0) oncarbon (50 mg) in ethanol (20 mL) was stirred at ambient temperatureunder hydrogen (balloon) for 3 h. The catalyst was removed by filtrationthrough Celite. The filtrate was concentrated to give the title compoundas an off white solid (150 mg, 74%). ¹H-NMR (400 MHz, CDCl₃/CD₃OD) δ7.25 (d, J=8.9 Hz, 1H), 7.13 (d, J=2.6 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H),6.85 (dd, J=8.9, 2.5 Hz, 1H), 6.38 (d, J=2.9 Hz, 1H), 4.43 (t, J=6.8 Hz,2H), 4.10 (t, J=5.8 Hz, 2H), 3.66 (s, 3H), 3.01 (q, J=7.0 Hz, 2H), 2.83(t, J=6.8 Hz, 2H), 2.04 (m, 2H).

c) Methyl 3-[5-(3-{[benzylamino]carbonylamino}propoxy)indolyl]propanoate

To the solution of methyl 3-[5-(aminopropoxy)indolyl]propanoate (140 mg,0.5 mmol), as prepared in the preceding step, in acetonitrile (10 mL)was added benzyl isocyanate (135 mg, 1.0 mmol), and the mixture wasstirred at ambient temperature overnight. After evaporating the solventin vacuo, the residue was purified by flash column chromatography onsilica gel (methylene chloride to 5% ethyl acetate in methylenechloride) to give the title compound as a white solid (85 mg, 42%).¹H-NMR (400 MHz, CDCl₃) δ 7.28 (m, 5H), 7.20 (d, J=8.9 Hz, 1H), 7.10 (d,J=2.8 Hz, 1H), 7.05 (d, J=2.5 Hz, 1H), 6.81 (dd, J=8.8, 2.5 Hz, 1H),6.38 (d, J=2.9 Hz, 1H), 4.66 (br s, 2H), 4.41 (t, J=6.8 Hz, 2H), 4.35(d, J=5.7 Hz, 2H), 4.06 (t, J=5.8 Hz, 2H), 3.66 (s, 3H), 3.43 (q, J=6.2Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 1.99 (t, J=6.1, 2H).

d) 3-[5-(3-{[Benzylamino]carbonylamino}propoxy)indolyl]propanoic acid

To the solution of methyl3-[5-(3-{[benzylamino]carbonylamino}propoxy)indolyl]propanoate (80 mg,0.2 mmol), as prepared in the preceding step, in tetrahydrofuran (5 mL)and water (5 mL) was added sodium hydroxide (20 mg), and the reactionmixture was stirred at ambient temperature for 2 h. After evaporatingthe tetrahydrofuran, the aqueous solution was acidified (pH 5-6), thewhite solid formed was collected, washed with water and dried under highvacuum to give the title compound (65 mg, 82%). ¹H-NMR (400 MHz, DMSO₆)δ 7.21 B 7.37 (m, 7H), 7.02 (d, J=2.4 Hz, 1H), 6.78 (dd, J=8.8, 2.4 Hz,1H), 6.36 (t, J=6.0 Hz, 1H), 6.30 (d, J=2.9 Hz, 1H), 6.06 (t, J=5.7 Hz,1H), 4.34 (t, J=6.8 Hz, 2H), 4.20 (d, J=6.0 Hz, 2H), 3.96 (t, J=6.2 Hz,2H), 3.19 (q, J=6.4 Hz, 2H), 2.71 (t, J=6.8 Hz, 2H), 1.83 (t, J=6.5 Hz,2H). Mass spectrum (LCMS, ESI) Calcd. for C₂₂H₂₅N₃O₄ 396.4 (M+H), found:396.1.

EXAMPLE 113-[5-(2-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl-acetylamino)-indol-1-yl]-hexanoicacid

a) (5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-acetic acid

To a solution of7-ethoxycarbonylmethyl-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (1.0 g, 3.12 mmol) in methanol (10 mL) was added asolution of NaOH (0.15 g, 3.75 mmol) in H₂O (1.0 mL), and stirred atambient temperature overnight. After evaporating the solvents, theresulting mixture was acidified to pH 3-4 with 1 N HCl, and extractedwith EtOAc (3 times). The extracts were combined, washed with brine,dried over sodium sulfate, concentrated and flash chromatographed onsilica gel, eluting with MeOH/DCM (1, 2.5, and 5%) to give the desiredacid (0.57 g, 63% yield) as a yellow solid. The solid (0.57 g, 1.95mmol) was dissolved DCM (5.0 mL), and TFA added (0.45 mL). Afterstirring at ambient temperature overnight, additional TFA (0.9 mL) wasadded, and the mixture stirred for 24 h. Solvents were evaporated,giving the title compound (0.60 g, quantitative yield) as a yellowsolid. Mass Spectrum (LCMS, ESI) calculated for C₁₀N₁₃N₂O₂ 193.1 (M+H);found 193.2.

b) 3-(5-Nitro-indol-1-yl)-hexanoic acid ethyl ester

The title compound was synthesized from 5-nitroindole using theprocedure described in Example 2, step (c), in 34% yield as an orangeoil. Mass spectrum (LCMS, ESI) calculated for C₁₆H₂₁N₂O₄ 305.3 (M+H);found 305.2.

c) 3-(5-Amino-indol-1-yl)-hexanoic acid ethyl ester

A mixture of 3-(5-nitro-indol-1-yl)-hexanoic acid ethyl ester (1.49 g,4.9 mmol), and 10% palladium on activated carbon (149 mg) in ethanol (15mL) was hydrogenated in a hydrogen balloon for 2 days. The mixture wasfiltered through Celite, and the Celite washed with methanol. Thefiltrate and washing were combined, concentrated, and flashchromatographed on silica gel, eluting with EtOAc/DCM (20, 30%) toafford the title compound (1.05 g, 78% yield) as dark brown oil. ¹H NMR(CDCl₃) δ 7.22 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=3.2 Hz), 6.90 (d, 1H,J=2.3 Hz), 6.66 (dd, 1H, J=2.2, 8.7 Hz), 6.33 (d, 1H, J=3.2 Hz),4.78-4.73 (m, 1H), 4.02-3.96 (m, 2H), 3.47 (bs, 2H), 2.87-2.74 (m, 2H),1.94-1.87 (m, 1H), 1.84-1.77 (m, 1H), 1.27-1.09 (m, 2H), 1.08 (t, 3H,J=7.1 Hz), 0.85 (t, 3H, J=7.3 Hz).

d)3-[5-(2-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl-acetylamino)-indol-1-yl]-hexanoicacid ethyl ester

A solution of (5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-acetic acid(0.2 g, 0.65 mmol), 3-(5-amino-indol-1-yl)-hexanoic acid ethyl ester(0.19 g, 0.71 mmol), BOP (0.35 g, 0.78 mmol), and diisopropylethylamine(0.45 mL, 2.6 mmol) in DMF (2.5 mL) was stirred for 16 h. Solvents wereevaporated. The resulting residue was partitioned between H₂O and EtOAc.The aqueous layer was separated and extracted once more with EtOAc. Theextracts were combined, washed with H₂O, brine, dried over Na₂SO₄,concentrated, and flash chromatographed on silica gel, eluting withEtOAc/DCM (15, 30, 50, and 80%) to give the title compound (0.20 g, 67%yield) as a brown oil. Mass spectrum (LCMS, ESI) calculated forC₂₆H₃₃N₄O₃ 449.3 (M+H); found 449.3.

e)3-[5-(2-5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl-acetylamino)-indol-1-yl]-hexanoicacid

To a solution of3-[5-(2-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-acetylamino)-indol-1-yl]-hexanoicacid ethyl ester (50 mg, 0.12 mmol) in THF (1.0 mL) was added a solutionof NaOH (18 mg, 0.45 mmol) in H₂O (0.15 mL), and stirred at ambienttemperature for 14 h. Solvents were evaporated. To the resulting residuewas added 1N HCl until the solution reached a pH of 5. The mixture wasextracted with EtOAc/DCM (9:1) several times until the aqueous layer wasfree from product by TLC. The extracts were combined, dried over Na₂SO₄,concentrated, and flash chromatographed on silica gel, eluting withMeOH/DCM (2.5, 5, and 7.5%) to afford the title compound (38 mg, 81%yield) as a pale brown solid. ¹H NMR (CDCl₃) δ 7.79 (d, 1H, J=1.9 Hz),7.57 (d, 1H, J=7.3 Hz), 7.45 (d, 1H, J=8.9 Hz,), 7.34 (d, 1H, J=3.2 Hz),7.23 (dd, 1H, J=2.0, 8.8 Hz), 6.69 (d, 1H, J=7.3 Hz), 6.46 (d, 1H, J=3.2Hz), 3.83 (s, 0.9H), 3.81 (s, 0.5H), 3.49 (t, 2H, J=5.6 Hz), 2.89 (d,2H, J=7.2 Hz), 2.83 (t, 2H, J=6.1 Hz), 2.67-1.86 (m, 4H), 1.19-0.99 (m,2H), 0.86 (t, 3H, J=7.3 Hz). Mass spectrum (LCMS, ESI) calculated forC₂₄H₂₉N₄O₃ 421.2 (M+H); found 421.3.

EXAMPLE 123-(5-{2-[N-(4,5-Dihydro-1H-imidazol-2-yl)-aminooxy]-ethoxy}-indol-1-yl)-3-phenyl-propionicacid

a) 5(2-Benzyloxy-ethoxy)-2-nitro-toluene

3-Methyl-4-nitrophenol (8.75 g, 57.1 mmol), 2-benzyloxyethanol (8.70 g,57.1 mmol) and triphenylphosphine (22.5 g, 85.1 mmol) were dissolved intetrahydrofuran (200 mL). The mixture was placed under argon at 0° C.and stirred for 10 minutes. Diisopropylazodicarboxylate (17.3 g, 58.1mmol) was added all at once. The reaction was stirred overnight (16 h).The solvent was removed under vacuum, and the crude mixture was purifiedvia column chromatography to give the product with reduceddiisopropylazodicarboxylate impurities. The impurities were eliminatedvia crystallization with hexane/ethyl acetate. The crystals werefiltered and the mother liquid was concentrated under vacuum to affordthe title compound (12.36 g, 75%) as oil. ¹H NMR (CDCl₃), δ 8.08 (d, 1H,J=9.7 Hz), 7.31-7.38 (m, 3H), 6.82 (m, 2H), 4.65 (s, 2H), 4.23 (t, 2H,J=4.9 Hz), 3.87 (t, 2H, J=4.9 Hz), 2.63 (s, 3H).

b) 5-(2-Benzyloxy-ethoxy)-1H-indole

5(2-Benzyloxy-ethoxy)-2-nitro-toluene (12.4 g, 43.0 mmol),N—N-dimethylfomamide dimethyl acetal (6.55 g, 51.6 mmol) and pyrrolidine(3.68 g, 51.6 mmol) were dissolved in N—N-dimethylfomamide (25 mL). Themixture was heated to 120° C. for 16 h. The solvent was evaporated undervacuum and the crude reaction was dissolved in 70% ethylacetate/methanol (250 mL). The reaction was placed in a ParrHydrogenator under a hydrogen atmosphere for 16 h with 10% palladium oncarbon [10% w/w] (3.00 g) at 50 psi. The reaction was filtrated overcelite and the crude mixture was purified via column chromatography withsilica gel eluting with hexane/ethyl acetate to give the title compound(22% yield). ¹H NMR (CDCl₃) δ 7.27-7.41 (m, 6H), 7.19 (t, 1H, J=2.5 Hz),7.13 (d, 1H, J=2.3 Hz), 6.91 (dd, 1H, J=2.5, 8.8 Hz), 6.48 (m, 1H), 4.67(s, 2H), 4.21 (m, 2H), 3.87 (m, 2H).

c) 3-[5-(2-Benzyloxy-ethoxy)-indol-1-yl]-3-phenyl-acrylic acid ethylester

5-(2-Benzyloxy-ethoxy)-1H-indole (2.20 g, 8.20 mmol) and ethyl phenylpropiolate (1.72 g, 9.80 mmol) were dissolved in tetrahydrofuran (5 mL)under an argon atmosphere. Tetrabutylammonium flouride [1M in THF] (20.5ml, 20.5 mmol) was added at once and the reaction was heated at 70° C.for 16 hr. The reaction was extracted with a mixture of ethyl acetateand brine. The organic layer was collected, dried (Na₂SO₄), filtered andevaporated under vacuum to give a crude mixture, which was purified viacolumn chromatography with silica gel, eluting with hexane/ethyl acetateto give the title compound (69% yield) as an E/Z isomeric mixture. ¹HNMR (CDCl₃), δ 7.30-7.53 (m, 10.7H), 7.09-7.13 (m, 2H), 6.97 (d, 0.3H,J=3.2 Hz), 6.78 (m, 1H), 6.61 (d, 0.7H, J=3.9 Hz), 6.24 (s, 0.7H), 6.17(s, 0.3H), 4.67 (s, 2H), 4.20 (m, 2H), 4.14 (c, 0.6H, J=7.2 Hz), 4.06(c, 1.4H, J=7.2 Hz), 3.87 (m, 2H), 1.18 (t, 0.9H, J=6.9 Hz), 1.05 (t,2.1H, J=7.2 Hz).

d) 3-[5-(2-Hydroxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethylester

3-[5-(2-benzyloxy-ethoxy)-indol-1-yl]-3-phenyl-acrylic acid ethyl ester(2.5 g, 5.6 mmol) was dissolved in 70% ethyl acetate/methanol (50 mL)and added under an argon atmosphere to a suspension of 10% palladium oncarbon [10% w/w] (3.0 g) in the same solvent (50 mL). The reaction wasplaced in a Parr Hydrogenator for 6 h. The reaction was filtered throughcelite and the solvent was evaporated under vacuum. Purification of thecrude mixture via column chromatography with silica gel, eluting withhexane/ethyl acetate gave the title compound (80% yield). ¹H NMR(CDCl₃), δ 7.14-7.32 (m, 7H), 6.82 (dd, 1H, J=2.3, 8.8 Hz), 6.45 (d, 1H,J=3.0 Hz), 6.07 (d, 1H, J=2.1 Hz), 6.01 (t, 1H, J=7.4 Hz), 4.03 (m, 4H),3.91 (m, 2H), 3.27 (m, 2H), 1.06 (t, 3H, J=7.2 Hz).

e)3-{5-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yloxy)-ethoxy]-indol-1-yl}-3-phenyl-propionicacid ethyl ester

3-[5-(2-hydroxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethyl ester(0.77 g, 2.10 mmol), N-hydroxyphthalimide (0.40 g, 2.40 mmol) andtriphenylphosphine (0.85 g, 3.24 mmol) were dissolved in tetrahydrofuran(5 mL). The mixture was placed under an argon atmosphere at 0° C. andstirred for 10 minutes. Diisopropylazodicarboxylate (0.65 g, 3.24 mmol)was added all at once. After stirring overnight (16 h), the solvent wasremoved under vacuum, and the crude mixture was purified via columnchromatography to afford the title compound (96% yield). ¹H NMR (CDCl₃)δ 7.79 (m, 2H), 7.70 (m, 2H), 7.15-7.29 (m, 7H), 7.03 (d, 1H, J=2.3 Hz),6.69 (dd, 1H, J=2.5, 9.0 Hz), 6.43 (d, 1H, J=3.7 Hz), 5.99 (t, 1H, J=7.7Hz), 4.56 (m, 2H), 4.34 (m, 2H), 4.02 (c, 2H, J=7.2 Hz), 3.27 (m, 2H),1.06 (t, 3H, J=7.2 Hz).

f) 3-[5-(2-Aminooxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethylester

3-{5-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethoxy]-indol-1-yl}-3-phenyl-propionicacid ethyl ester (1.0 g, 2.0 mmol) was dissolved in tetrahydrofuran (4mL) at room temperature. Dimethylamine [1.0 M in THF] (10 mL, 10 mmol)was added and the reaction stirred at room temperature for 16 h. Thesolvent was evaporated under vacuum and the crude mixture was purifiedvia column chromatography with silica gel to afford the title compound(73% yield). ¹H NMR (CDCl₃) δ 7.15-7.28 (m, 7H), 7.08 (d, 1H, J=2.5 Hz),6.84 (dd, 1H, J=2.3, 8.8 Hz), 6.45 (d, 1H, J=2.3 Hz), 6.00 (t, 1H, J=7.7Hz), 4.56 (m, 2H), 4.15 (m, 2H), 4.00 (m, 4H), 3.26 (m, 2H), 1.06 (t,3H, J=7.2 Hz).

g)3-(5-{2-[N-(4,5-Dihydro-1H-imidazol-2-yl)-aminooxy]-ethoxy}-indol-1-yl)-3-phenyl-propionicacid ethyl ester

3-[5-(2-aminooxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethyl ester(208 mg, 0.56 mmol) and 2-(3,5-dimethylpyrazolyl)-4,5-dihydroimidizolehydrobromide (125 mg, 0.90 mmol) were dissolved in methanol (3 mL) andstirred for 5 days. The solvent was evaporated under vacuum and thecrude mixture was purified via column chromatography with silica gel,eluting with 10% methanol in dichloromethane to afford the titlecompound (99% yield). ¹H NMR (CDCl₃) δ 7.16-7.29 (m, 7H), 7.07 (d, 1H,J=2.3 Hz), 6.80 (dd, 1H, J=2.3, 8.8 Hz), 6.47 (d, 1H, J=3.2 Hz), 6.00(t, 1H, J=7.0 Hz), 4.24 (m, 2H), 4.17 (m, 2H), 4.03 (c, 2H, J=7.2 Hz),3.51 (br s, 4H), 3.26 (m, 2H), 1.09 (t, 3H, J=7.2 Hz).

h).3-(5-{2-[N-(4,5-Dihydro-1H-imidazol-2-yl)-aminooxy]-ethoxy}-indol-1-yl)-3-phenyl-propionicacid

3-(5-{2-[N-(4,5-dihydro-1H-imidazol-2-yl)-aminooxy]-ethoxy}-indol-1-yl)-3-phenyl-propionicacid ethyl ester (0.24 g, 0.55 mmol) was dissolved in 70% methanol/water(4 mL). Lithium hydroxide monohydratate (0.70 g, 4.67 mmol) was addedand the reaction was stirred for 16 h at room temperature under an argonatmosphere. The solution was neutralized with 1.0 N HCl (4.67 mL) andthe solvent was evaporated under vacuum. The crude mixture was purifiedvia column chromatography with silica gel, eluting with 10%methanol/dichloromethane to afford the title compound (74% yield). ¹HNMR (DMSO-d6) δ 7.68 (d, 1H, J=3.2 Hz), 7.42 (d, 1H, J=9.0 Hz),7.20-7.34 (m, 5H), 7.05 (d, 1H, J=2.5 Hz), 6.75 (dd, 1H, J=2.5, 9.0 Hz),6.40 (d, 1H, J=3.0 Hz), 5.96 (m, 1H), 4.16 (m, 4H), 3.59 (br s, 4H),3.36 (m, 2H). Mass Spectrum (LCMS, ESI) calculate for C₂₂H₂₅N₄O₄ 409.2(M+H); found 409.2.

EXAMPLE 133-(5-{2-[Guanidino-oxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic acid

a) 3-(5-{2-[Guanidino-oxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic acidethyl ester

3-[5-(2-aminooxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethyl ester(0.28 g, 0.75 mmol) and 1H-pyrazole-1-carboxamide hydrochloride (0.99 g,0.67 mmol) were dissolved in methanol (3 mL) and stirred for 5 days. Thesolvent was evaporated under vacuum and the crude mixture was purifiedvia column chromatography with silica gel, eluting with 10%methanol/dichloromethane to afford the title compound (97% yield). ¹HNMR (CDCl₃), δ 7.11-7.26 (m, 7H), 7.00 (d, 1H, J=2.3 Hz), 6.75 (dd, 1H,J=2.3, 8.8 Hz), 6.43 (d, 1H, J=3.2 Hz), 5.98 (t, 1H, J=7.6 Hz), 4.08 (m,2H), 3.99 (m, 4H), 3.23 (m, 2H), 1.05 (t, 3H, J=7.2 Hz).

b) 3-(5-{2-[Guanidino-oxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic acid

3-(5-{2-[guanidino-oxy]-ethoxy}-indol-1-yl)-3-phenyl-propionic acidethyl ester (0.30 gg, 0.71 mmol) was dissolved in 70% methanol/water (4mL) and lithium hydroxide monohydratate (0.70 g, 4.67 mmol) was added.The reaction was stirred for 16 h at room temperature under an argonatmosphere. The solution was neutralized with 1.0 N HCl (4.67 mL) andthe solvent was evaporated under vacuum. The crude mixture was purifiedvia column chromatography with silica gel, eluting with 10%methanol/dichloromethane to afford the title compound (80% yield). ¹HNMR (CD₃OD-d4) δ 7.34 (d, 1H, J=3.2 Hz). 7.06-7.15 (m, 6H), 6.97 (d, 1H,J=2.3 Hz), 6.65 (dd, 1H, J=2.5, 9.0 Hz), 6.31 (d, 1H, J=3.2 Hz), 5.93(t, 1H, J=7.0 Hz), 4.01 (m, 4H), 3.07 (m, 2H).

EXAMPLE 143-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoicacid

a) 3-(5-Benzyloxy-indol-1-yl)-hexanoic acid ethyl ester

A solution of 5-benzyloxyindole (5.00 g, 22.4 mmol) in DMF (20 mL) wasadded dropwise to a stirred solution of sodium hydride (0.91 g, 38.1mmol) in DMF (50 mL) at 0° C. and stirred for 20 minutes.Ethyl-1-bromocaproate (5.59 g, 26.9 mmol) in DMF (20 mL) was added andthe reaction was stirred at room temperature overnight. The reaction wasthen poured into cold H₂O (150 mL) and extracted with ethyl acetate(3×50 mL), dried over magnesium sulfate and concentrated. The residuewas purified by flash chromatography on silica gel (40% ethyl acetate inhexane) to give the title compound as oil (40% yield). ¹H NMR (CDCl₃) δ7.47 (d, 2H, J=7.2 Hz), 7.38 (t, 2H, J=7.1 Hz), 7.32 (d, 2H, J=8.8 Hz),7.12 (dd, 2H, J=2.4, 13.7 Hz), 6.94 (dd, 1H, J=2.4, 10.2 Hz), 6.44 (d,1H, J=3.1 Hz), 5.09 (s, 2H), 4.79 (m, 1H), 3.98 (q, 2H, J=7.1 Hz), 2.80(m, 2H), 1.90 (m, 2H), 1.25 (m, 2H), 1.07 (t, 3H, J=7.2 Hz), 0.86 (t,3H, J=7.3 Hz).

b) 3-(5-Hydroxy-indol-1-yl)-hexanoic acid ethyl ester

Palladium (0) on carbon [10% w/w] (0.20 g) was added to a solution of(5-benzyloxy-indol-1-yl)-hexanoic acid ethyl ester (2.00 g, 5.47 mmol)in methanol (10 mL) under an argon atmosphere. The reaction was placedunder H₂ atmosphere and stirred overnight. The solution was filteredthrough a bed of celite and concentrated. The residue was purified byflash chromatography on silica gel (10% ethyl acetate in hexane) to givethe title compound as a solid (93% yield). ¹H NMR (CDCl₃) δ 7.30 (d, 2H,J=8.8 Hz), 7.12 (m, 1H), 7.00 (m, 1H), 6.75 (m, 1H), 6.45 (m, 1H), 4.80(m, 1H), 4.72 (s, 1H), 3.95 (q, 2H, J=7.2 Hz), 2.80 (m, 2H), 1.84 (m,2H), 1.28 (m, 2H), 1.10 (t, 3H, J=7.2 Hz), 0.90 (t, 3H, J=7.2 Hz).

c)7-{2-[1-(1-Ethoxycarbonylmethyl-butyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

Triphenylphosphine (0.20 g, 0.77 mmol) was added to a solution of7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acidtert-butyl ester (0.16 g, 0.58 mmol) and3-(5-hydroxy-indol-1-yl)-hexanoic acid ethyl ester (0.10 g, 0.38 mmol)in THF (4 mL) at 0° C. Diisopropylazodicarboxylate (0.15 g, 0.77 mmol)was added dropwise and the reaction was stirred at room temperatureovernight. The solution was then concentrated. The residue was purifiedby flash chromatography on silica gel (30% ethyl acetate in hexane) togive the title compound (13% yield). ¹H NMR (CDCl₃) δ 7.30 (m, 2H), 7.09(m, 2H), 6.96 (d, 1H, J=7.6 Hz), 6.86 (m, 1H), 6.41 (d, 1H, J=3.2 Hz),4.78 (m, 1H), 4.39 (t, 2H, J=6.9 Hz), 3.98 (q, 2H, J=7.1 Hz), 3.75 (m,2H), 3.21 (t, 2H, J=6.9 Hz), 2.86 (m, 2H), 2.77 (m, 2H), 1.85 (m, 4H),1.50 (s, 9H), 1.20 (m, 2H), 1.06 (t, 3H, J=7.1 Hz), 0.85 (t, 3H, J=7.4Hz).

d)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoicacid ethyl ester

7-{2-[1-(1-Ethoxycarbonylmethyl-butyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (0.02 g, 0.04 mmol) was heated neat to 200° C. for15 minutes. The residue was purified by flash chromatography on silicagel (ethyl acetate) to give the title compound (90% yield). ¹H NMR(CDCl₃) δ 7.28 (m, 1H), 7.08 (m, 3H), 6.86 (m, 1H), 6.48 (d, 1H, J=8.0Hz), 6.41 (d, 1H, J=4.0 Hz), 4.84 (s, 1H), 4.78 (m, 1H), 4.29 (t, 2H,J=4.0 Hz), 3.98 (q, 2H, J=8.0 Hz), 3.39 (m, 2H), 3.04 (t, 2H, J=8.0 Hz),2.81 (m, 2H), 2.69 (t, 2H, J=8.0 Hz), 1.93 (m, 4H), 1.25 (m, 2H), 1.10(t, 3H), 0.85 (t, 3H).

e)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoicacid

Sodium hydroxide (0.01 g, 0.23 mmol) was added to a solution of3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoicacid ethyl ester (0.02 g, 0.04 mmol) in methanol/water (9/1, 1 mL) andstirred overnight. The reaction was acidified to pH 6 with 1N HCl andthe crude product was extracted with ethyl acetate (3×10 mL) andconcentrated. The residue was purified by flash chromatography on silicagel (10% methanol in ethyl acetate) to give the title compound (28%yield). ¹H NMR (CDCl₃) δ 10.4 (bs, 1H), 7.38 (d, 1H, J=8.0 Hz), 7.21 (d,1H, J=3.2 Hz), 7.14 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=2.3 Hz), 6.73 (m,1H), 6.48 (d, 1H, J=7.3 Hz), 6.32 (d, 2H, J=3.0 Hz), 4.80 (s, 1H), 4.22(t, 2H, J=7.0 Hz), 3.47 (m, 2H), 2.95 (t, 2H, J=6.8 Hz), 2.68 (m, 4H),1.88 (m, 4H), 1.15 (m, 2H), 0.81 (t, 3H, J=7.4 Hz). Mass Spectrum (LCMS,ESI) calculated for C₂₄H₃₀N₃O₃ 408.2 (M+H); found 408.3.

EXAMPLE 153-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a)7-{2-[1-(2-Ethoxycarbonyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acidtert-butyl ester and ethyl 2-(5-hydroxyindolyl)propanoate using theprocedure described in Example 14, step (c), in 20% yield. ¹H NMR(CDCl₃) δ 7.32 (d, J=7.62 Hz, 1H), 7.21 (d, J=8.87 Hz, 1H), 7.11 (d, 1H,J=2.3 Hz), 7.08 (d, 1H, J=3.10 Hz), 6.95 (d, 1H, J=7.60 Hz), 6.88 (dd,1H, J=2.4, 8.9 Hz), 6.37 (dd, 1H, J=0.6, 3.1 Hz), 4.42-4.36 (m, 2H),4.11 (q, 2H, J=7.2 Hz), 3.76 (dd, 2H, J=6.0, 7.2 Hz), 3.21 (t, 2H, J=6.9Hz), 2.79 (t, 2H, J=6.9 Hz), 2.73 (t, 2H, J=6.7 Hz), 1.92 (p, 2H, J=6.6Hz), 1.52 (s, 9H), 1.20 (t, 3H, J=7.1 Hz).

b)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 14, step(d), in 50% yield. ¹H NMR (CDCl₃) δ 7.21 (d, 1H, J=8.9 Hz), 7.11-7.07(m, 3H), 6.88 (dd, 1H, J=2.4, 8.8 Hz), 6.48 (d, 1H, J=7.3 Hz), 6.37 (dd,1H, J=0.7, 3.1 Hz), 4.81 (bs, 1H), 4.40 (t, 2H, J=6.9 Hz), 4.30 (t, 2H,J=7.3 Hz, 2H), 4.11 (q, 2H, J=7.1 Hz), 3.42-3.38 (m, 2H), 3.42-3.38 (m,2H), 3.04 (t, 2H, J=7.0 Hz), 2.79 (t, 2H, J=6.9 Hz), 2.70 (t, 2H, J=6.3Hz), 1.94-1.88 (m, 2H), 1.20 (t, 3H, J=7.2 Hz). Mass spectrum (LCMS,ESI) calculated for C₂₃H₂₈N₃O₃ 394.2 (M+H); found 394.3.

c)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 14, step (e),in 99% yield. ¹H NMR (CDCl₃) δ 8.83 (bs, 1H), 7.30-7.27 (m, 1H), 7.18(d, 1H, J=8.9 Hz), 7.16 (d, 1H, J=3.1 Hz), 7.01 (d, 1H, J=2.3 Hz), 6.77(dd, 1H, J=2.3, 8.8 Hz), 6.50 (d, 1H, J=7.3 Hz), 6.31 (d, 1H, J=3.0 Hz),4.33 (t, 2H, J=6.8 Hz), 4.25 (t, 2H, J=5.8 Hz), 3.42 (t, 2H, J=5.4 Hz),3.11 (t, 2H, J=5.8 Hz), 2.76 (t, 2H, J=6.7 Hz), 2.70 (t, 2H, J=6.1 Hz),1.87 (p, 2H, J=6.1 Hz). Mass Spectrum (LCMS, ESI) calculated forC₂₁N₂₄N₃O₃ 366.2 (M+H); found 366.3.

EXAMPLE 163-Phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 7-(2-Hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

7-Ethoxycarbonylmethyl-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (synthetic methodology described in PublishedInternational Patent Appl. WO 00/33838) (6.11 g, 19.0 mmol) wasdissolved in tetrahydrofuran (40 mL) at room temperature. The solutionwas place under argon. Lithium borohydride [2M in tetrahydrofuran] (22.8mmol, 11.43 mL) was carefully added and the reaction was refluxedovernight (16 h). The mixture was poured into a solution of saturatedammonium chloride and extracted with ethyl acetate. The organic layerwas dried over Na₂SO₄, filtered, and evaporated under vacuum to give acrude mixture, which was purified via column chromatography to give7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acidtert-butyl ester (49% yield). ¹H NMR(Cl₃CD), δ: 7.30 (d, 1H, J=7.6 Hz),7.76(d, 1H, J=7.6 Hz), 3.98 (m, 2H), 3.78 (m, 2H), 2.92 (m, 2H), 2.71(m, 2H), 1.92(m, 2H), 1.54 (s, 9H).

b)7-[2-(3-Methyl-4-nitro-phenoxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

An ice-cooled solution of7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acidtert-butyl ester (100 g, 359 mmol), 3-methyl-4-nitrophenol (45.7 g, 298mmol), and triphenylphosphine (157 g, 597 mmol) in anhydrous THF (1.5 L)was stirred under an atmosphere of nitrogen for 15 min. To this solutionwas added diisopropylazodicarboxylate (118 mL, 597 mmol) over 5 minutesand the mixture was allowed to gradually warm up and stir at roomtemperature for 16 h. The mixture was filtered to remove the insolublematerial and the filtrate was concentrated in vacuo and re-dissolved indiethyl ether (1 L) to remove most of the reduceddiisopropylazodicarboxylate and triphenylphosphine oxide (125 g) byfiltration. The ether solution was concentrated in vacuo to give a gum(286 g) as the crude product. The crude product was filtered through aplug of silica gel (1 Kg) using 2:1 ether/pet-ether as eluent to removedthe remaining triphenylphosphine. The fractions from the plug werecombined and concentrated to 1 L, which resulted in the crystallizationof the title compound (91 g, 61% yield). ¹H NMR (CDCl₃), δ 8.05 (d, 1H,J=8.8 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.89 (d, 1H, J=7.6 Hz), 6.81 (m, 2H),4.44 (t, 2H, J=8.00 Hz), 3.76 (m, 2H), 3.20 (t, 2H, J=8.00 Hz), 2.73 (m,2H), 2.61 (s, 3H), 1.93 (m, 2H), 1.51 (s, 9H).

c)7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

Treatment of7-[2-(3-methyl-4-nitro-phenoxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (14.0 g, 33.9 mmol) with N,N-dimethylformamidedimethyl acetal (5.40 mL, 40.7 mmol) and pyrrolidine (3.37 mL, 40.7mmol) in DMF (20 mL) at 75° C. gave a deep orange solution after 16 h.After that period the solvent was removed under vacuum to yield a redgum (15.5 g) corresponding with7-{2-[4-Nitro-3-(2-pyrrolidin-1-yl-vinyl)-phenoxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester. This compound was used in the next step withoutfurther purification. 15.5 g of crude7-{2-[4-Nitro-3-(2-pyrrolidin-1-yl-vinyl)-phenoxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester was dissolved in a 9:1 solution of EtOAc/MeOH in aParr bottle. After evacuating and purging the solution with nitrogen,palladium on carbon [10% w/w] (1.52 g) was added and the mixture wasshaken under an atmosphere of hydrogen at 50 psi overnight (16 h). Themixture was filtered through Celite and washed with methanol. Thefiltrate was concentrated in vacuo to afford a brown gum (15.8 g). Thecrude product was purified by column chromatography (SiO₂, 4:1 to 2:1heptane/ethyl acetate) to give7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester as a gray solid contaminated with an impurity. Thesolid washed with 1:1 ether/pet-ether (30 mL) to give the title compound(7.14 g, 54% yield) as a pure white solid. ¹H NMR (CDCl₃) δ 7.31 (d, 1H,J=7.6 Hz), 7.26 (d, 1H, J=8.8 Hz), 7.17 (m, 1H), 7.13 (d, 1H, J=2.4 Hz),6.96 (d, 1H, J=7.6 Hz), 6.85 (dd, 1H, J=2.4, 8.8 Hz), 6.45 (m, 1H), 4.38(t, 2H, J=8.00 Hz), 3.76 (m, 2H,), 3.22 (t, 2H, J=8.00 Hz), 2.73 (m,2H), 1.93 (m, 2H), 1.51 (s, 9H).

d)7-{2-[1-(2-Ethoxycarbonyl-1-phenyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

Method d1

CsF (15.2 g, 100 mmol) was added to a solution of7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (20.0 g, 50.8 mmol) in anhydrous DMF (50 mL).Ethyl phenylpropionate (16.5 mL, 100 mmol) was added to the mixture atroom temperature and the solution was allowed to stir under a nitrogenatmosphere at 60° C. for 4 h. The mixture was diluted with water (1 L),the crude mixture was dissolved in ethyl acetate (500 mL), washed withwater, then brine, dried and concentrated under vacuum to give a yellowgum as crude product. Purification of the crude mixture on silica gel(1:1 pet-ether/ether) gave the title compound as a bright yellow solid(25.5 g, 88% yield), a mixture of E/Z isomers.

Method d2

A mixture of7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (5.00 g, 12.7 mmol), phenyl-propionic acid ethylester (4.43 g, 25.4 mmol), and tetrabutylammonium fluoride [1.0 M inTHF] (31.8 mL, 31.8 mmol) was stirred at 75° C. for 3 days. Afterremoval of solvent, the crude reaction mixture was submitted to flashchromatography on silica gel (ethyl acetate/hexane, 1:4) to give thetitle compound (4.66 g, 78% yield) as an E/Z mixture. ¹H NMR (CDCl₃)[E/Z mixture] δ 7.50-7.30 (m, 7H), 7.20 (m, 2H), 7.05 (m, 1H), 6.80 (m,1H), 6.56 (m, 1H), 6.29 (s, 0.5H), 6.19 (s, 0.5H), 4.44 (m, 2H), 4.07(q, 2H, J=6.8 Hz), 3.82 (m, 2H), 3.31 (m, 2H), 2.70 (m, 2H), 1.98 (m,2H), 1.54 (s, 9H), 1.13 (t, 1.5H, J=7.2 Hz), 1.01 (t, 3H, J=7.2 Hz).

e)7-{2-[1-(2-Ethoxycarbonyl-1-phenyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

10% Palladium on activated carbon (0.06 g) was added to7-{2-[1-(2-ethoxycarbonyl-1-phenyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (0.50 g, 0.88 mmol) in methanol (10 mL) underargon. The solution was exposed to a hydrogen atmosphere (50 psi) usinga Parr shaker for 24 h. The reaction was filtered through celite andwashed with methanol. The filtrate was concentrated in vacuo to yieldthe title compound (0.48 g, 98%). ¹H NMR (CDCl₃) δ 7.15-7.36 (m, 9H),6.96 (d, 1H, J=7.6 Hz), 6.83 (dd, 1H, J=2.3, 6.6 Hz), 6.46 (d, 1H, J=3.0Hz), 6.06 (d, 1H, J=7.6 Hz), 4.39 (m, 2H), 4.06 (q, 2H, J=7.1 Hz), 3.78(m, 2H), 3.31-3.20 (m, 4H), 2.75 (m, 2H), 1.94 (m, 2H), 1.54 (s, 9H),1.11 (t, 3H, J=7.1 Hz).

f)3-Phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

A solution of7-{2-[1-(2-ethoxycarbonyl-1-phenyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (22.9 g, 40.0 mmol) in a 10:1 mixture of anhydroustoluene/DMF (220 mL) was treated with copper (I)trifluoromethanesulfonate benzene complex [30% w/w] (6.87 g) at 130° C.for 75 minutes. The mixture was cooled to room temperature, diluted withwater (200 mL), extracted with dichloromethane (2×300 mL), washed withwater, then brine, dried and concentrated under vacuum to give a blackgum (26.0 g). Purification with silica gel (1:1 ethyl acetate/heptane)gave the title compound as an off-white solid (16.2 g, 86% yield). ¹HNMR (CDCl₃) δ 7.29-6.98 (m, 10H), 6.73 (m, 1H), 6.36 (m, 1H), 5.94 (t,1H, J=7.5 Hz), 4.69 (bs, 1H), 4.21 (t, 2H, J=7.0 Hz), 3.96 (q, 2H, J=7.1Hz), 3.32 (m, 2H), 3.20 (m, 2H), 2.96 (t, 2H, J=7.0 Hz), 2.61 (m, 2H),1.83 (m, 2H), 1.00 (t, 3H, J=7.2 Hz).

g)3-Phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

A solution of3-phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester (2.14 g, 4.49 mmol) in a 2:1:0.2 THF/MeOH/H₂O (67 mL)was treated with lithium hydroxide monohydrate (0.38 g, 9.00 mmol) atroom temperature. The reaction was stirred for 20 h. The mixture wasdiluted with ethyl acetate, acidified to pH 4 (0.5 N HCl), washed withwater and brine, dried and concentrated to afford a crude mixture (2.02g), which was purified by column chromatography with silica gel (39:1 to29:1 dichloromethane/MeOH) to give the title compound (1.31 g, 66%yield). ¹H NMR (CDCl₃) δ 10.5 (s, 1H), 7.44 (d, 1H, J=3.1 Hz), 7.20-7.00(m, 7H), 6.76 (m, 1H), 6.53 (dd, 1H, J=2.3, 6.6 Hz), 6.41 (s, 1H), 6.19(d, 1H, J=7.3 Hz), 6.07 (dd, 1H, J=4.3, 7.1 Hz), 3.68 (m, 1H), 3.52 (m,1H), 3.33 (m, 3H), 3.25-3.09 (m, 2H), 2.58 (m, 3H), 1.77 (m, 3H). MassSpectrum (LCMS, ESI) calculated for C₂₇H₂₈N₃O₃ 442.2 (M+H); found 442.3.

EXAMPLE 173-Phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 3-(5-Benzyloxy-indol-1-yl)-3-phenyl-acrylic acid ethyl ester

A mixture of 5-benzyloxy-1H-indole (4.46 g, 20.0 mmol), phenyl-propionicacid ethyl ester (7.00 g, 40.0 mmol), and tetrabutylammonium fluoride[1.0 M in THF] (36.0 mL, 50.0 mmol) was stirred for 3 days. Afterremoval of solvent, the crude reaction mixture was submitted to flashchromatography on silica gel with ethyl acetate/hexane (1:4) to give thetitle compound (5.42 g, 68% yield) as an E/Z isomeric mixture. MassSpectrum (LCMS, ESI) calculated for C₂₆H₂₄NO₃ 398.2 (M+H); found 398.2.

b) 3-(5-Hydroxy-indol-1-yl)-3-phenyl-propionic acid ethyl ester

A mixture of 3-(5-benzyloxy-indol-1-yl)-3-phenyl-acrylic acid ethylester (1.94 g, 4.89 mmol) and palladium on carbon [10% w/w] (60 mg) inmethanol (25 mL) was stirred under hydrogen atmosphere for 24 h. Afterremoval of the catalyst by filtration, the crude product was purified byflash chromatography on silica gel with hexane/ethyl:acetate (4:1) togive the title compound in 96% yield. ¹H NMR (CDCl₃) δ 7.10-7.30 (m,7H), 6.99 (d, J=2.4 Hz, 1H), 6.69 (dd, J=2.4 and 8.7 Hz, 1H), 6.39 (d,J=3.2 Hz, 1H), 5.99 (t, J=7.6 Hz, 1H), 5.31 (br, 1H), 4.03 (q, J=7.2 Hz,2H), 3.26 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). ¹³C NMR (CDCl₃) δ 170.4,149.7, 139.8, 131.5, 129.3, 128.8, 127.9, 126.2, 125.8, 111.6, 110.6,105.2, 101.4, 61.1, 56.2, 40.4, 13.9. Mass Spectrum (LCMS, ESI)calculated for C₁₉H₂₀NO₃ 310.1 (M+H); found 310.1.

c)7-{2-[1-(2-Ethoxycarbonyl-1-phenyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized as an E/Z isomeric mixture from3-(5-hydroxy-indol-1-yl)-3-phenyl-propionic acid ethyl ester using theprocedure described in Example 16, step (d2), in 81% yield. MassSpectrum (LCMS, ESI) calculated for C₂₉H₃₀N₃O₃ 468.2 (M-Boc+H); found469.4.

d)7-{2-[1-(2-Ethoxycarbonyl-1-phenyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from3-(5-hydroxy-indol-1-yl)-3-phenyl-propionic acid ethyl ester using theprocedure described in Example 14, step (b), in 24% yield. ¹H NMR(CDCl₃) δ 7.28 (m, 4H), 7.18 (m, 4H), 7.09 (d, J=2.9 Hz, 1H), 6.93 (d,J=7.7 Hz, 1H), 6.80 (dd, J=2.5 and 7.9 Hz, 1H), 6.43 (dd, J=0.6 and 3.2Hz, 1H), 6.00 (m, 1H), 4.35 (t, J=6.9 Hz, 2H), 4.02 (q, J=7.0 Hz, 2H),3.75 (m, 2H), 3.26 (q, 2H), 3.19 (t, J=6.9 Hz, 2H), 2.71 (t, J=6.7 Hz,2H), 1.92 (m, 2H), 1.51 (s, 9H), 1.08 (t, J=7.1 Hz, 3H). Mass Spectrum(LCMS, ESI) calculated for C₃₄H₄₀N₃O₅ 570.2 (M+H), found 570.0 (M+H).

e)3-Phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-phenyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 14, step(d), in 43% yield. ¹H NMR (CDCl₃) δ 7.29 (m, 3H), 7.19 (m, 4H), 7.08 (m,2H), 6.81 (dd, J=2.4 and 8.9 Hz, 1H), 6.45 (m, 2H), 6.03 (t, 1H), 4.86(br, 1H), 4.28 (t, J=7.1 Hz, 2H), 4.06 (q, J=6.1 Hz, 2H), 3.39 (m, 2H),3.27 (m, 2H), 3.04 (t, J=7.0 Hz, 2H), 2.68 (t, J=6.3 Hz, 2H), 1.88 (m,2H), 1.08 (t, J=7.1 Hz, 3H). Mass Spectrum (LCMS, ESI) calculated forC₂₉H₃₂N₃O₃ 470.2 (M+H); found 470.3.

f)3-Phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-phenyl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 14, step (e),in 51% yield. ¹H NMR (CDCl₃) δ 10.59 (br, 1H), 7.08-7.27 (m, 8H), 6.84(d, J=2.4 Hz, 1H), 6.61 (dd, J=2.4 and 8.9 Hz, 1H), 6.48 (m, 1H), 6.26(d, J=7.3 Hz, 1H), 6.13 (dd, J=4.4 Hz, 1H), 3.59 (m, 1H), 3.17-3.42 (m,5H), 2.40-2.64 (m, 4H), 1.84 (m, 2H). Mass Spectrum (LCMS, ESI)calculated for C₂₇H₂₈N₃O₃ 442.2 (M+H); found 442.4.

EXAMPLE 183-(3-Benzyloxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) (3-Benzyloxy-phenylethynyl)-trimethyl-silane

To a solution of 3-benzyloxy-1-iodophenyl (8.40 g, 27.0 mmol),trimethylsilyl acetylene (4.21 mL, 29.8 mmol), copper (I) iodide (0.51g, 2.71 mmol), and triethylamine (8.22 mL, 81.2 mmol) in dichloromethane(30 mL) was added dichlorobis(triphenylphosphine) palladium(II) (0.38 g,5.41 mmol) portionwise over a 3 minute period, and the reaction mixturestirred overnight. The mixture was then concentrated and the resultingresidue was filtered through Celite. The filtrate was concentrated, andpurified via column chromatography with silica gel, eluting withdichloromethane/hexane/ethyl acetate (10/1) to give the title compound(98% yield) as pale yellow oil. ¹H NMR (CDCl₃) δ 7.43-7.32 (m, 5H), 7.19(m, 1H), 7.08 (m, 2H), 6.92 (m, 1H), 5.04 (s, 2H), 0.24 (s, 9H).

b) 3-Benzyloxy-phenylethynyl

Tetrabutylammonium fluoride [1.0 M in THF] (28.0 mL) was added dropwiseat room temperature to a solution of(3-benzyloxy-phenylethynyl)-trimethyl-silane (6.40 g, 22.7 mmol) inaqueous THF (30 mL) and the reaction was stirred for 1 hour. Water (100mL) was added and the crude product was extracted with ethyl acetate(3×50 mL), dried over magnesium sulfate and concentrated. The crudemixture was then purified via column chromatography with silica gel (10%ethyl acetate in hexane) to give the title compound (89% yield). ¹H NMR(CDCl₃) δ 7.42-7.29 (m, 5H), 7.21 (m, 1H), 7.09 (m, 2H), 6.95 (m, 1H),5.03 (s, 2H), 3.04 (s, 1H).

c) 3-(3-Benzyloxy-phenyl)-3-chloro-acrylic acid ethyl ester

A mixture of ethyl chloroformate (2.90 mL, 26.7 mmol),3-benzyloxy-phenylethynyl (2.50 g, 8.91 mmol), andcarbonylchlorobis-(triphenylphosphine)-rhodium(I) (0.03 g, 0.05 mmol) intoluene (10 mL) was heated under argon at 110° C. for 12 h. The solventwas removed under reduced pressure and the crude product was purified bychromatography on silica gel, eluting with hexane/ethyl acetate (10/1)to give the title compound (50%) as yellow oil. ¹H NMR (CDCl₃) δ7.48-7.28 (m, 8H), 7.06 (m, 1H), 6.57 (s, 1H), 5.12 (s, 2H), 4.31 (q,2H, J=7.1 Hz), 1.37 (t, 3H, J=7.1 Hz).

d)7-(2-{1-[1-(3-Benzyloxy-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

A solution of7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (0.20 g, 0.51 mmol),7-(2-{1-[1-(3-benzyloxy-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (0.18 g, 0.56 mmol), potassium phosphate (0.16 g,0.77 mmol), 2-dicyclohexylphosphino-2′(N,N-dimethylamino)biphenyl (0.03g, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.03 mg,0.08 mmol) in 10% DMF/toluene (3 mL) was heated at 110° C. for 6 daysunder argon. The reaction was cooled to room temperature and the solventwas removed under reduced pressure. The crude product was purified bycolumn chromatography with silica gel, eluting with hexane/ethyl acetate(4/1) to give the title compound (29%) as an E/Z isomeric mixture. ¹HNMR (CDCl₃) [E/Z mixture] δ 7.36-7.22 (m, 7H), 7.10 (m, 4H), 6.86 (m,3H), 6.75 (m, 1H), 6.58 (m, 1H), 6.22 (s, 1H), 5.00 (s, 2H), 4.40 (m,2H), 4.01 (q, 2H, J=7.2 Hz), 3.78 (m, 2H), 3.22 (m, 2H), 2.75 (m, 2H),1.85 (m, 2H), 1.52 (s, 9H), 1.01 (t, 3H, J=6.8 Hz).

e)7-(2-{1-[1-(3-Benzyloxy-phenyl)-2-ethoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

Samarium (II) iodide [0.1 M in THF] (14.8 mL, 14.8 mmol) was added to asolution of7-(2-{1-[1-(3-benzyloxy-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester (0.10 g, 0.15 mmol), hexamethylphosphoramide (0.39mL, 2.22 mmol) and either ethanol or methanol (10 equivalents) andstirred at room temperature overnight. Saturated ammonium chloride (20mL) was added to the reaction and the crude product was extracted withethyl acetate (3×20 mL). The crude mixture was then purified via columnchromatography in silica gel (20% ethyl acetate in hexane) to give thetitle compound (0.50 g, 50% yield). ¹H NMR (CDCl₃) δ 7.28-7.22 (m, 5H),7.13 (m, 4H), 7.08 (d, 1H, J=3.2 Hz), 6.86 (m, 1H), 6.79-6.69 (m, 4H),6.35 (d, 1H, J=3.2 Hz), 5.99 (t, 1H, J=7.5 Hz), 4.98 (s, 2H), 4.29 (t,2H, J=6.9 Hz), 3.96 (q, 2H, J=7.1 Hz), 3.68 (m, 2H), 3.18-3.10 (m, 4H),2.66 (m, 2H), 1.85 (m, 2H), 1.45 (s, 9H), 1.01 (t, 3H, J=7.1 Hz).

f)3-(3-Benzyloxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-(2-{1-[1-(3-benzyloxy-phenyl)-2-ethoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 43% yield. ¹H NMR (CDCl₃) δ 7.36-7.32 (m, 4H), 7.17-7.07 (m,6H), 6.77 (m, 4H), 6.43 (m, 2H), 5.99 (m, 1H), 4.96 (s, 2H), 4.90 (bs,1H), 4.28 (m, 2H), 4.03 (q, 2H, J=7.1 Hz), 3.39 (m, 2H), 3.23 (m, 2H),2.68 (m, 2H), 2.52 (m, 2H), 1.89 (m, 2H), 1.01 (t, 3H, J=7.1 Hz).

g)3-(3-Benzyloxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

A solution of3-(3-benzyloxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester (0.08 g, 0.14 mmol), lithium hydroxide (0.01 g, 0.22mmol) and THF/methanol/water [2.0/1.0/0.2 mL] (3.2 mL) was microwave at100° C. for 15 minutes. Saturated ammonium chloride was added (10 mL)and the product was extracted with ethyl acetate (3×10 mL). The crudeproduct was purified via column chromatography eluting withdichloromethane:ethyl acetate (10:1) to give the title compound (25%yield) as white solid. ¹H NMR (CDCl₃) δ 10.5 (bs, 1H), 7.49 (d, 1H,J=3.0 Hz), 7.39-7.22 (m, 6H), 7.16 (m, 1H), 7.08 (m, 1H), 6.80 (m, 4H),6.60 (dd, 1H, J=2.2, 6.8 Hz), 6.46 (m, 1H), 6.26 (d, 1H, J=7.3 Hz), 6.09(m, 1H), 5.29 (s, 2H), 3.59 (s, 1H), 3.38 (m, 3H), 3.29-3.14 (m, 2H),2.60-2.43 (m, 5H), 1.87 (m, 2H). Mass Spectrum (LCMS, ESI) calculatedfor C₃₄H₃₄N₃O₄ 548.3 (M+H); found 548.4.

EXAMPLE 193-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-p-tolyl-propionicacid

a) 1-Ethynyl-4-methyl-benzene

The title compound was synthesized from commercially available4-iodotoluene using the procedures outlined in Example 18, step (a) andstep (b), in 60% yield overall. ¹H NMR (CDCl₃) δ 7.38 (d, 2H, J=2.4 Hz),7.12 (d, 2H, J=2.4 Hz), 3.02 (s, 1H), 2.35 (s, 3H).

b) 3-Chloro-3-p-tolyl-acrylic acid ethyl ester

The title compound was synthesized from 1-ethynyl-4-methyl-benzene usingthe procedure outlined in Example 18, step (c), in 70% yield. ¹H NMR(CDCl₃) δ 7.58 (d, 2H, J=2.4 Hz), 7.21 (d, 2H, J=2.4 Hz), 6.52 (s, 1H),4.27 (m, 2H), 2.39 (s, 3H), 1.33 (t, 3H, J=7.2 Hz).

c)7-{2-[1-(2-Ethoxycarbonyl-1-p-tolyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from 3-chloro-3-p-tolyl-acrylic acidethyl ester and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure outlined in Example 18, step(d), in a 36% yield of E/Z isomeric mixture. ¹H NMR (CDCl₃) [E/Zmixture] δ 7.33 (m, 1.4H), 7.17 (m, 4.6H), 6.96 (m, 1.6H), 6.74 (m,2.4H), 6.57 (d, 0.8H, J=0.8 Hz), 6.50 (d, 0.2H, J=0.8 Hz), 6.20 (s,0.8H), 6.11 (s, 0.2H), 4.39 (t, 2H, J=8.0), 4.01 (m, 2H), 3.78 (t, 2H,J=4.0), 3.22 (t, 2H, J=8.0), 2.75 (t, 2H, J=8.0), 2.44 (s, 0.6H), 2.40(s, 2.4H), 1.94 (m, 2H), 1.53 (s, 9H), 1.05 (t, 3H, J=8.0 Hz).

d)7-{2-[1-(2-Ethoxycarbonyl-1-p-tolyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-p-tolyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure outlined in Example 18, step(e). Transesterification occurred during the reduction, resulting in a1:4 mixture of ethyl and methyl esters, in a 60% yield. ¹H NMR (CDCl₃) δ7.30 (d, 1H, J=7.2 Hz), 7.18 (m, 2H), 7.10 (m, 5H), 6.94 (d, 1H, J=7.6Hz), 6.80 (dd, 1H, J=2.4, 7.6 Hz), 6.41 (d, 1H, J=3.2 Hz), 5.98 (t, 1H,J=7.6 Hz), 4.35 (t, 2H, J=6.8 Hz), 4.13 (m, 0.4H, ethyl ester), 3.77 (m,2H), 3.59 (s, 2.4H, methyl ester), 3.27 (m, 2H), 3.20 (t, 2H, J=6.8 Hz),2.72 (t, 2H, J=6.8 Hz), 2.31, (s, 3H), 1.95 (m, 2H), 1.49 (s, 9H), 1.11(t, 0.6H, J=7.2 Hz, ethyl ester).

e)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-p-tolyl-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(2-Ethoxycarbonyl-1-p-tolyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure outlined in Example 16, step(f), in a 78% yield of a 1:1 mixture of ethyl and methyl esters. ¹H NMR(CDCl₃) δ 7.16 (m, 3H), 7.08 (m, 5H), 6.81 (dd, 1H, J=2.4, 9.6 Hz), 6.48(d, 1H, J=8.0 Hz), 6.43(d, 1H, J=4.0 Hz), 5.98 (t, 1H, J=8.0 Hz), 5.17(s, 1H), 4.27 (t, 2H, J=8.0 Hz), 4.03 (m, 1H, ethyl ester), 3.59 (s,1.5H, methyl ester) 3.39 (m, 2H), 3.25 (m, 2H), 3.07 (t, 2H, J=8.0 Hz),2.69 (t, 2H, J=6.8 Hz), 2.29 (s, 3H), 1.90 (m, 2H), 1.10 (t, 1.5H, J=7.2Hz, ethyl ester).

f)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-p-tolyl-propionicacid

The title compound was synthesized from3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-p-tolyl-propionicacid ethyl ester using the procedure outlined in Example 18, step (g),in 23% yield. ¹H NMR (DMSO-d₆) δ 7.62 (d, 1H, J=3.2 Hz), 7.35 (d, 1H,J=9.0 Hz), 7.20 (d, 2H, J=8.1 Hz), 7.06 (m, 3H), 7.01(d, 1H, J=4.0 Hz),6.69 (dd, 1H, J=2.4, 6.5 Hz), 6.36 (m, 3H), 5.89 (m, 1H), 4.19 (t, 2H,J=6.9 Hz), 3.25 (m, 4H) 2.86 (t, 2H, J=6.9 Hz), 2.60 (t, 2H, J=6.1 Hz),2.21 (s, 3H), 1.74 (m, 2H). Mass Spectrum (LCMS, ESI) calculated forC₂₈H₃₀N₃O₃: 456.2 (M+H); found 456.3.

EXAMPLE 203-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-m-tolyl-propionicacid

a) 1-Ethynyl-3-methyl-benzene

The title compound was synthesized from commercially available3-iodotoluene using the procedures outlined in Example 18, step (a) andstep (b), in 37% yield overall. ¹H NMR (CDCl₃) δ 7.32 (m, 2H), 7.18 (m,2H), 3.03 (s, 1H), 2.32 (s, 3H).

b) 3-Chloro-3-m-tolyl-acrylic acid ethyl ester

The title compound was synthesized from 1-ethynyl-3-methyl-benzene usingthe procedure outlined in Example 18, step (c), in 70% yield. ¹H NMR(CDCl₃) δ 7.48 (m, 2H), 7.29 (m, 2H), 6.53 (s, 1H), 4.27 (m, J=8.0 Hz),2.39 (s, 3H), 1.34 (t, 3H, J=7.2 Hz).

c)7-{2-[1-(2-Ethoxycarbonyl-1-m-tolyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from 3-chloro-3-m-tolyl-acrylic acidethyl ester and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure outlined in Example 18, step(d), in a 40% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) δ 7.19(m, 2.2H), 7.04 (m, 2.6H), 6.96 (m, 1.6H), 6.86 (m, 1.6H), 6.66 (m, 2H),6.48 (d, 0.8H, J=0.8 Hz), 6.40 (d, 0.2H, J=0.8 Hz), 6.11 (s, 0.8H), 6.04(s, 0.2H), 4.30 (m, 2H), 3.93 (m, 2H), 3.68 (m, 2H), 3.13 (t, 2H,J=6.4), 2.65 (t, 2H, J=6.4 Hz), 2.24 (s, 3H), 1.85 (m, 2H), 1.43 (s,9H), 0.94 (t, 3H, J=6.8 Hz).

d)7-{2-[1-(2-Ethoxycarbonyl-1-p-tolyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-m-tolyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure outlined in Example 18, step(e). Transesterification occurred during the reduction, resulting in a2:3 mixture of ethyl and methyl esters, in a 58% yield. ¹H NMR (CDCl₃) δ7.31 (d, 1H, J=4.4 Hz), 7.21 (m, 3H), 7.05 (m, 5H), 6.83 (dd, 1H, J=2.4,9.6 Hz), 6.48 (d, 1H, J=3.2 Hz), 5.99 (t, 1H, J=7.6 Hz), 4.37 (t, 2H,J=7.0 Hz), 4.05 (m, 0.8H, ethyl ester), 3.77 (m, 2H), 3.60 (s, 1.8H,methyl ester) 3.28 (m, 2H), 3.21 (t, 2H, J=6.8 Hz), 2.74 (t, 2H, J=6.8Hz), 2.29 (s, 3H), 1.93 (m, 2H), 1.52 (s, 9H), 1.10 (t, 1.2H, J=7.2 Hz,ethyl ester).

e)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-m-tolyl-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-p-tolyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in a 75% yield of a 1:1 mixture of ethyl and methyl ester. ¹H NMR(CDCl₃) δ 7.19 (m, 4H), 7.05 (m, 5H), 6.81 (dd, 1H, J=2.4, 9.6 Hz), 6.48(d, 1H, J=8.0 Hz), 6.43(d, 1H, J=3.2 Hz), 5.97 (t, 1H, J=8.0 Hz), 5.30(s, 1H), 4.29 (t, 2H, J=8.0 Hz), 4.05 (m, 1H, ethyl ester), 3.59 (s,1.5H, methyl ester) 3.39 (t, 2H, J=8.0 Hz), 3.25 (m, 2H), 3.04 (t, 2H,J=8.0 Hz), 2.69 (t, 2H, J=6.8 Hz), 2.28 (s, 3H), 1.90 (m, 2H), 1.08 (t,1.5H, J=8.0 Hz, ethyl ester).

f)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-m-tolyl-propionicacid

The title compound synthesized from3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-m-tolyl-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 37% yield. ¹H NMR (CDCl₃) δ 10.39 (s, 1H), 7.43 (d, 1H, J=4.0 Hz),7.20 (d, 1H, J=8.0 Hz), 7.05 (m, 2H), 6.90 (m, 3H), 6.77(d, 1H, J=4.0Hz), 6.54 (dd, 1H, J=4.0, 8.0 Hz), 6.40 (d, 1H, J=4.0 Hz), 6.19 (d, 1H,J=8.0 Hz), 6.02 (dd, 1H, J=4.0, 8.0 Hz), 3.25 (m, 6H) 2.45 (m, 4H), 2.19(m, 3H), 1.76 (m, 2H). Mass Spectrum (LCMS, ESI) calculated forC₂₈H₃₀N₃O₃: 456.2 (M+H); found 456.3.

EXAMPLE 213-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-o-tolyl-propionicacid

a) 1-Ethynyl-2-methyl-benzene

The title compound was synthesized from commercially available2-iodotoluene using the procedures outlined in Example 18, step (a) andstep (b), in 45% yield overall. ¹H NMR (CDCl₃) δ 7.45 (m, 1H), 7.24 (m,2H), 7.13 (m, 1H), 3.26 (s, 1H), 2.45 (s, 3H).

b) 3-Chloro-3-o-tolyl-acrylic acid ethyl ester

The title compound was synthesized from 1-ethynyl-2-methyl-benzene usingthe procedure outlined in Example 18, step (c), in 70% yield. ¹H NMR(CDCl₃) δ 7.25 (m, 5H), 6.17 (s, 1H), 4.27 (m, 2H), 2.40 (s, 3H), 1.34(t, 3H, J=7.2 Hz).

c)7-{2-[1-(2-Ethoxycarbonyl-1-o-tolyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from 3-chloro-3-o-tolyl-acrylic acidethyl ester and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure outlined in Example 18, step(d), in a 35% yield of an E/Z isomeric mixture. ¹H NMR (CDCl₃) δ 7.46(m, 0.6H), 7.30 (m, 4.8H), 7.10 (m, 1.6H), 7.03 (d, 0.6H, J=3.6 Hz),6.94 (m, 1H), 6.85 (m, 0.4H), 6.70 (m, 1H), 6.53 (d, 0.8H, J=2.8 Hz),6.47 (d, 0.2H, J=2.8 Hz), 6.30 (s, 0.2H), 5.82 (s, 0.8H), 4.39 (m, 2H),4.10 (m, 2H), 3.78 (m, 2H), 3.22 (t, 2H, J=6.8), 2.75 (t, 2H, J=6.8),2.07 (s, 2.4H), 2.02 (s, 0.6H), 1.94 (m, 2H), 1.53 (s, 9H), 1.05 (m,3H).

d)7-{2-[1-(2-Ethoxycarbonyl-1-o-tolyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-o-tolyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e). Transesterification occurred during the reduction, resulting in a4:1 mixture of ethyl and methyl ester in a 72% yield. ¹H NMR (CDCl₃) δ7.25 (m, 7H), 7.15 (d, 1H, J=2.4 Hz), 7.05 (m, 2H), 6.85 (dd, 1H, J=2.4,9.6 Hz), 6.39 (d, 1H, J=3.2 Hz), 5.99 (t, 1H, J=7.6 Hz), 4.38 (t, 2H,J=7.0 Hz), 4.03 (m, 1.6H, ethyl ester), 3.77 (m, 2H), 3.60 (s, 0.6H,methyl ester), 3.21 (m, 4H), 2.74 (t, 2H, J=6.8 Hz), 2.40 (s, 3H), 1.93(m, 2H), 1.53 (s, 9H), 1.10 (t, 2.4H, J=7.2 Hz, ethyl ester).

e)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-p-tolyl-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-o-tolyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in a 75% yield of a 1:1 mixture of ethyl and methyl esters. ¹H NMR(CDCl₃) δ 7.17 (m, 5H), 7.05 (m, 2H), 6.94 (d, 1H, J=3.2 Hz), 6.81 (dd,1H, J=2.4, 6.4 Hz), 6.46 (d, 1H, J=7.6 Hz), 6.34 (d, 1H, J=3.2 Hz), 6.13(t, 1H, J=7.2 Hz), 4.91 (s, 1H), 4.26 (t, 2H, J=6.8 Hz), 4.10 (m, 1H,ethyl ester), 3.56 (s, 1.5H, methyl ester), 3.38 (m, 2H), 3.17 (t, 2H,J=7.2 Hz), 3.08 (t, 2H, J=1.2 Hz), 2.67 (t, 2H, J=6.8 Hz), 2.20 (s, 3H),1.88 (m, 2H), 1.07 (t, 1.5H, J=7.2 Hz).

f)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-o-tolyl-propionicacid

The title compound was synthesized from3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-p-tolyl-propionicacid ethyl ester using the procedure outlined in Example 18, step (g),in 30% yield. ¹H NMR (DMSO-d₆) δ 7.49 (d, 1H, J=3.2 Hz), 7.33 (s, 1H),7.14 (m, 5H), 7.05 (d, 1H, J=2.4 Hz), 6.69 (dd, 1H, J=2.4, 6.5 Hz), 6.55(d, 1H, J=6.8 Hz), 6.38 (d, 1H, J=3.2 Hz), 6.06 (m, 1H), 4.21 (t, 2H,J=6.5 Hz), 3.21 (m, 4H) 2.99 (t, 2H, J=6.0 Hz), 2.67 (t, 2H, J=6.0 Hz),2.34 (s, 3H), 1.77 (m, 2H). Mass Spectrum (LCMS, ESI) calculated forC₂₈H₃₀N₃O₃: 456.2 (M+H); found 456.3.

EXAMPLE 223-Biphenyl-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 3-Biphenyl-4-yl-3-chloro-acrylic acid ethyl ester

The title compound was synthesized from the commercially available4-ethynyl-biphenyl using the procedure described in Example, 18 step(c), in 22% yield. ¹H NMR (Cl₃CD), δ: 7.76 (m, 2H), 7.61 (m, 5H), 7.45(m, 2H), 6.60 (s, 1H), 4.29 (c, 2H, J=8.0 Hz), 1.34 (t, 3H, J=7.2 Hz).

b)7-{2-[1-(1-Biphenyl-4-yl-2-ethoxycarbonyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester and 3-biphenyl-4-yl-3-chloro-acrylic acid ethylester using the procedure described in Example 18, step (d), in an 8%yield as a mixture of E/Z isomers.

¹H NMR (Cl₃CD), δ: 7.65 (m, 2H), 7.59 (m, 3H), 7.46 (m, 4H), 7.37 (m,0.35H), 7.32 (d, 1H, J=7.6 Hz), 7.12 (d, 0.65H, J=2.5 Hz), 7.09 (m, 1H),6.99 (d, 0.35H, J=3.5 Hz), 6.95 (d, 0.65H, J=7.6 Hz), 6.94 (d, 0.35H,J=7.6 Hz), 6.80 (d, 0.65H, J=9.0 Hz), 6.78 (dd, 0.35H, J=2.5, 9.0 Hz),6.72 (dd, 0.65H, J=2.3, 8.8 Hz), 6.59 (d, 0.65H, J=3.5 Hz), 6.51 (d,0.35H, J=3.2 Hz), 6.27 (s, 0.65H), 6.16 (s, 0.35H), 4.38 (m, 2H), 4.12(c, 1.3H, J=8.0 Hz), 4.00 (c, 0.7H, J=8.0 Hz), 3.76 (m, 2H), 2.73 (t,2H, J=8 Hz), 3.21 (m, 2H), 1.92 (m, 2H), 1.52 (m, 9H), 1.28 (t, 1.95H,J=8.0 Hz), 1.18 (t, 1.05H, J=8.0 Hz).

c)7-{2-[1-(1-Biphenyl-4-yl-2-ethoxycarbonyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-(1-biphenyl-4-yl-2-ethoxycarbonyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 59% yield. ¹H NMR (Cl₃CD), δ: 7.43 (m, 4H), 7.33 (m, 2H), 7.25(m, 2H), 7.15 (m, 4H), 7.02 (d, 1H, J=2.3 Hz), 6.88 (d, 1H, J=7.4 Hz),6.76 (dd, 1H, J=2.5, 9.0 Hz), 6.38 (d, 1H, J=3.2 Hz), 5.98 (t, 1H, J=7.4Hz), 4.29 (m, 2H), 3.98 (c, 2H, J=7.2 Hz), 3.36 (m, 2H), 3.68 (m, 2H),3.13 (m, 2H), 2.65 (m, 2H), 1.92 (m, 2H), 1.44 (s, 9H), 1.18 (t, 3H,J=7.2 Hz).

d)3-Biphenyl-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(1-biphenyl-4-yl-2-ethoxycarbonyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 43% yield. ¹H NMR (Cl₃CD), δ: 7.44 (m, 4H), 7.34 (m, 3H), 7.26(m, 1H), 7.16 (m, 4H), 7.02 (d, 1H, J=2.1 Hz), 6.73 (dd, 1H, J=2.3, 8.8Hz), 6.41 (d, 1H, J=3.0 Hz), 5.98 (t, 1H, J=7.7 Hz), 4.23 (t, 2H, J=6.0Hz), 3.98 (c, 2H, J=6.92 Hz), 3.68 (m, 2H), 3.37 (m, 2H), 3.05 (t, 2H,J=6.3 Hz), 2.64 (t, 2H, J=6.3 Hz), 1.83 (m, 2H), 1.03 (t, 3H, J=6.9 Hz).

e)3-Biphenyl-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-biphenyl-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 83% yield. ¹H NMR (Cl₃CD), δ: 7.45 (m, 3H), 7.39 (m, 2H), 7.32 (m,2H), 7.24 (m, 2H), 7.15 (d, 1H, J=8.3 Hz), 7.02 (d, 1H, J=7.2 Hz), 6.80(d, 1H, J=2.3 Hz), 6.57 (dd, 1H, J=2.3, 8.8 Hz), 6.44 (m, 1H), 6.19 (d,1H, J=7.4 Hz), 6.11 (m, 1H), 3.54 (m, 2H), 3.32 (m, 2H), 3.18 (m, 2H),2.55 (m, 4H), 1.76 (m, 2H). Mass Spectrum (LCMS, ESI) calculate forC₃₃H₃₂N₃O₃: 518.2, (M+1); found: 518.4.

EXAMPLE 233-(3,5-dichloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) (3,5-Dichloro-phenylethynyl)-trimethyl-silane

The title compound was synthesized from 1,3-dichloro-5-iodo-benzeneusing the procedure described in Example 18, step (a), in 98% yield. ¹HNMR (CDCl₃) δ 7.34-7.33 (m, 2H), 7.31-7.29 (m, 1H), 0.24 (s, 9H).

b) 1,3-Dichloro-5-ethynyl-benzene

To a solution of (3,5-dichloro-phenylethynyl)-trimethyl-silane (1.97 g,8.1 mmol) in methanol (40 mL) was added a solution of potassiumhydroxide (6.8 mg, 0.12 mmol) in H₂O (0.24 mL). After stirring atambient temperature for 40 minutes, the reaction mixture was dilutedwith water (40 mL), and extracted with hexane until the extractingsolvent showing no product by TLC. The combined organic layer was driedover MgSO₄, and concentrated to give the title compound (1.21 g, 87%yield) as a white solid. ¹H NMR (CDCl₃) δ 7.37-7.34 (m, 3H), 3.15 (s,1H).

c) (3,5-Dichloro-phenyl)-propynoic acid ethyl ester

To a solution of diisopropylamine (0.23 mL) in THF (0.6 mL) at −78° C.was added a solution of n-butyllithium (0.46 mL, 2.0 M in hexane). Themixture was stirred at −78° C. for 20 minutes, 0° C. for 15 min., andcooled to −78° C. To this mixture was added a solution of1,3-dichloro-5-ethynyl-benzene (136 mg, 0.80 mmol) in THF (1.0 mL) over2 minutes. After stirring at −78° C. for 1 h, a solution of ethylchloroformate (0.09 mL) in THF (0.2 mL) was added, and stirred for 1 hat −78° C. The reaction was quenched with saturated ammonium chloride,warmed up to ambient temperature, and extracted with ethyl acetate. Theextract was dried over Na₂SO₄, concentrated, and flash chromatographedon silica gel, eluting with hexane to give the title compound (0.16 g,87% yield) as a yellow oil. ¹H NMR (CDCl₃) δ 7.47-7.44 (m, 3H), 4.31 (q,2H, J=7.2 Hz), 1.36 (t, 3H, J=7.2 Hz).

d)7-(2-{1-[1-(3,5-Dichloro-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (3,5-dichloro-phenyl)-propynoicacid ethyl ester using the procedure described in Example 16, step (d1),in 43% yield as a mixture of E/Z isomers. ¹H NMR (CDCl₃) δ 7.49-7.43 (m,1H), 7.32 (d, 1H, J=7.6 Hz), 7.27 (d, 1H, J=1.9 Hz), 7.18-7.15 (m, 1H),7.10-7.00 (m, 1H), 6.96-6.93 (m, 1H), 6.85 (d, 1H, J=3.5 Hz), 6.83-6.76(m, 1H), 6.59 (d, 0.2H, J=3.4 Hz), 6.52 (d, 0.8H, J=3.5 Hz), 6.20 (s,0.2H), 6.19 (s, 0.8H), 4.41-4.36 (m, 2H), 4.12 (q, 2H, J=7.1 Hz), 3.76(t, 2H, J=5.6 Hz), 3.21 (t, 2H, J=6.8 Hz), 2.74 (t, 2H, J=6.6 Hz),1.96-1.90 (m, 2H), 1.52 (s, 9H), 1.26 (t, 3H, J=7.2 Hz).

e)7-(2-{1-[1-(3,5-Dichloro-phenyl)-2-ethoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[1-(3,5-dichloro-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 75% yield. ¹H NMR (CDCl₃) δ 7.31 (d, 1H, J=7.6 Hz), 7.25-7.24(m, 2H), 7.17-7.10 (m, 3H), 7.04-7.03 (m, 2H), 6.94 (d, 1H, J=7.6 Hz),6.84 (dd, 1H, J=2.4, 8.9 Hz), 6.48 (d, 1H, J=3.2 Hz), 5.93 (t, 1H, J=7.5Hz), 4.37 (t, 2H, J=6.9 Hz), 4.10-4.04 (m, 2H), 3.76 (t, 2H, J=6.0 Hz),3.30-3.16 (m, 4H), 2.73 (t, 2H, J=6.6 Hz), 1.92 (p, 2H, J=6.6 Hz), 1.50(s, 9H), 1.12 (t, 3H, J=7.1 Hz).

f)3-(3,5-Dichloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from7-(2-{1-[1-(3,5-dichloro-phenyl)-2-ethoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester in two steps using the procedures described inExample 16, step (f), and Example 18, step (e), in 41% yield. ¹H NMR(CDCl₃) δ 10.35 (bs, 1H), 7.44 (d, 1H, J=3.2 Hz), 7.19-7.11 (m, 3H),7.04-7.02 (m, 2H), 6.87 (d, 1H, J=2.2 Hz), 6.63 (dd, 1H, J=2.2, 8.9 Hz),6.49 (d, 1H, J=3.0 Hz), 6.29 (d, 1H, J=7.3 Hz), 6.05 (dd, 1H, J=4.8,10.5 Hz), 3.73-3.67 (m, 1H), 3.56-3.51 (m, 1H), 3.48-3.37 (m, 2H),3.26-3.08 (m, 2H), 2.70-2.53 (m, 4H), 1.85-1.82 (m, 2H). Mass Spectrum(LCMS, ESI) calculated for C₂₇H₂₅Cl₂N₃O₃ 510.1 (M+H); found 510.4.

EXAMPLE 243-(3,5-Difluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) (3,5-Difluoro-phenylethynyl)-trimethyl-silane

The title compound was synthesized from 1,3-difluoro-5-bromobenzeneusing the procedure described in Example 18, step (a), in 96% yield. ¹HNMR (CDCl₃) δ 7.02-6.93 (m, 2H), 6.80-6.74 (m, 1H), 0.25 (s, 9H).

b) 1-Ethynyl-3,5-difluoro-benzene

The title compound was synthesized from(3,5-difluoro-phenylethynyl)-trimethyl-silane using the proceduredescribed in Example 23, step (b), in 79% yield. ¹H NMR (CDCl₃) δ7.04-6.97 (m, 2H), 6.85-6.80 (m, 1H), 3.14 (s, 1H).

c) (3,5-Difluoro-phenyl)-propynoic acid ethyl ester

The title compound was synthesized from 1-ethynyl-3,5-difluoro-benzeneusing the procedure described in Example 23, step (c), in 69% yield. ¹HNMR (CDCl₃) δ 7.13-7.07 (m, 2H), 6.92 (tt, 1H, J=2.3, 8.8 Hz), 4.31 (q,2H, J=7.2 Hz), 1.36 (t, 3H, J=7.2 Hz).

d)7-(2-{1-[1-(3,5-Difluoro-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (3,5-difluoro-phenyl)-propynoicacid ethyl ester using the procedure described in Example 16, step (d1),in 47% yield, as a mixture of E/Z isomers. ¹H NMR (CDCl₃) δ 7.33-7.31(m, 1H), 7.13-7.08 (m, 1H), 7.02 (d, 1H, J=3.3 Hz), 6.95-6.80 (m, 4H),6.75-6.74 (m, 2H), 6.58 (d, 0.54H, J=3.4 Hz), 6.52 (dd, 0.46H, J=0.6,3.5 Hz), 6.23 (s, 0.54H), 6.18 (s, 0.46H), 4.41-4.36 (m, 2H), 4.00 (q,2H, J=7.1 Hz), 3.76 (t, 2H, J=6.0 Hz), 3.21 (t, 2H, J=6.9 Hz), 2.73 (t,2H, J=6.6 Hz), 1.96-1.89 (m, 2H), 1.52 (s, 9H), 1.02 (t, 3H, J=7.1 Hz).

e)7-(2-{1-[1-(3,5-Difluoro-phenyl)-2-methoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[1-(3,5-difluoro-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 71% yield. ¹H NMR (CDCl₃) δ 7.30 (d, 1H, J=7.6 Hz), 7.25-7.10(m, 3H), 6.94-6.92 (m, 1H), 6.84-6.82 (m, 1H), 6.70-6.65 (m, 3H), 6.47(d, 1H, J=3.3 Hz), 5.96 (t, 1H, J=7.9 Hz), 4.38-4.35 (m, 2H), 3.76-3.74(m, 2H), 3.63 (s, 3H), 3.33-3.18 (m, 4H), 2.74-2.70 (m, 2H), 1.95-1.88m, 2H), 1.51 (s, 9H).

f)3-(3,5-Difluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester

The title compound was synthesized from7-(2-{1-[1-(3,5-difluoro-phenyl)-2-ethoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 95% yield. Mass Spectrum (LCMS, ESI) calculated for C₂₈H₂₈F₂N₃O₃492.2 (M+H); found 492.4.

g)3-(3,5-Difluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-(3,5-difluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 80% yield. ¹H NMR (DMSO-d₆) δ 7.72 (d, 1H, J=3.3 Hz), 7.48 (d, 1H,J=8.9 Hz), 7.21 (d, 1H, J=7.0 Hz), 7.12-7.08 (m, 3H), 7.04 (d, 1H, J=2.3Hz), 6.72 (dd, 1H, J=2.4, 8.9 Hz), 6.46 (d, 1H, J=7.5 Hz), 6.41 (d, 1H,J=3.3 Hz), 6.00 (dd, 1H, J=5.6, 9.3 Hz), 4.21 (t, 2H, J=6.8 Hz),3.50-3.28 (m, 4H), 2.94 (t, 2H, J=6.4 Hz), 2.64 (t, 2H, J=5.9 Hz), 1.76(p, 2H, J=5.8 Hz). Mass Spectrum (LCMS, ESI) calculated for C₂₇H₂₆F₂N₃O₃478.2 (M+H); found 478.3.

EXAMPLE 253-(3-cyano-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 3-Trimethylsilanylethynyl-benzonitrile

The title compound was synthesized from 3-bromobenzonitrile using theprocedure described in Example 18, step (a), in 99% yield. ¹H NMR(CDCl₃) δ7.74 (dt, 1H, J=0.6, 6.3 Hz), 7.68-7.65 (m, 1H), 7.60-7.65 (m,1H), 7.44-7.40 (m, 1H), 0.26 (s, 9H).

b) 3-Ethynyl-benzonitrile

The title compound was synthesized from3-trimethylsilanylethynyl-benzonitrile using the procedure described inExample 23, step (b), in 90% yield. ¹H NMR (CDCl₃) *7.77 (t, 1H, J=1.4Hz), 7.70 (td, 1H, J=1.3, 7.8 Hz), 7.63 (td, 1H, J=1.4, 7.8 Hz), 7.45(dt, 1H, J=0.4, 7.9 Hz), 3.19 (s, 1H).

c) (3-Cyano-phenyl)-propynoic acid ethyl ester

The title compound was synthesized from 3-ethynyl-benzonitrile using theprocedure described in Example 23, step (c), in 80% yield. ¹H NMR(CDCl₃) *6.87-6.86 (m, 1H), 7.80 (td, 1H, J=1.3, 7.9 Hz), 7.73 (td, 1H,J=1.3, 7.9 Hz), 7.53 (t, 1H, J=7.9 Hz), 4.32 (q, 2H, J=7.2 Hz), 1.37 (t,3H, J=7.2 Hz).

d)7-(2-{1-[1-(3-Cyano-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (3-cyanophenyl)propynoic acidethyl ester using the procedure described in Example 16, step (c1), in71% yield as a mixture of E/Z isomers. ¹H NMR (CDCl₃) *7.79-7.48 (m,4H), 7.33-7.31 (m, 1H), 7.13-7.10 (m, 1H), 7.06-7.02 (m, 1H), 6.94 (dd,1H, J=2.3, 7.6 Hz), 6.84-6.79 (m, 1H), 6.75-6.66 (m, 1H), 6.60 (dd,0.56H, J=0.6, 3.3 Hz), 6.53 (dd, 0.44H, J=0.5, 3.5 Hz), 6.23 (s, 0.6H),6.22 (s, 0.4H), 4.41-4.36 (m, 2H), 4.11 (q, 0.9H, J=7.1 Hz), 4.03 (q,1.1H, J=7.1 Hz), 3.78-3.75 (m, 2H), 3.21 (t, 2H, J=6.9 Hz), 2.73 (t, 2H,J=6.7 Hz), 1.92 (p, 2H, J=6.6 Hz), 1.52 (s, 9H), 1.20 (t, 1.3H, J=7.1Hz), 1.04 (t, 1.7H, J=7.2 Hz).

e)7-(2-{1-[1-(3-Cyano-phenyl)-2-ethoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[1-(3-cyano-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 80% yield as a mixture of ethyl and methyl esters. ¹H NMR(CDCl₃) *7.56-7.53 (m, 1H), 7.45-7.30 (m, 4H), 7.18-7.17 (m, 1H),7.11-7.08 (m, 2H), 6.94 (d, 1H, J=7.6 Hz), 6.82 (dd, 1H, J=2.4, 8.9 Hz),6.49 (d, 1H, J=3.2 Hz), 6.02 (t, 1H, J=7.5 Hz), 4.36 (t, 2H, J=6.9 Hz),4.08 (q, 0.52H, J=7.1 Hz), 3.77-3.74 (m, 2H), 3.65 (s, 2.2H), 3.36-3.18(m, 4H), 2.73 (t, 2H, J=6.6 Hz), 1.95-1.87 (m, 2H), 1.52 (s, 9H), 1.12(t, 0.8H, J=7.1 Hz).

f)3-(3-Cyano-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from3-(3-cyano-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 16, step (e),in 50% yield as a white solid. ¹H NMR (CDCl₃) *7.56-7.53 (m, 1H),7.45-7.34 (m, 3H), 7.17 (t, 1H, J=3.0 Hz), 7.10-7.08 (m, 3H), 6.82 (dd,1H, J=2.4, 8.9 Hz), 6.49-6.46 (m, 2H), 6.02 (t, 1H, J=7.5 Hz), 5.04 (bs,1H), 4.28 (t, 2H, J=6.8 Hz), 4.07 (q, 0.6H, J=6.2 Hz), 3.63 (s, 2.1H),3.42-3.39 (m, 2H), 3.35-3.22 (m, 4H), 3.03 (t, 2H, J=6.9 Hz), 2.69 (t,2H, J=6.3 Hz), 1.93-1.87 (m, 2H), 1.12 (t, 0.9H, J=7.1 Hz). MassSpectrum (LCMS, ESI) calculated for C₂₉H₂₉N₄O₃ 481.2 (methyl ester,M+H); found 481.4. Calculated for C₃₀H₃₁N₄O₃ 495.2 (ethyl ester, M+H);found 495.3.

The title compound was synthesized from7-(2-{1-[1-(3-cyano-phenyl)-2-ethoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(g), in 50% yield as a pale yellow solid. ¹H NMR (CDCl₃) *9.72 (bs, 1H),7.47 (d, 1H, J=6.5 Hz), 7.38-7.30 (m, 4H), 7.19 (d, 1H, J=7.3 Hz), 7.11(d, 1H, J=8.9 Hz), 6.89 (bs, 1H), 6.64 (d, 1H, J=8.7 Hz), 6.48 (d, 1H,J=2.5 Hz), 6.35 (d, 1H, J=7.3 Hz), 6.09 (dd, 1H, J=5.5, 9.5 Hz),3.85-3.68 (m, 2H), 3.38-3.35 (m, 2H), 3.29-3.13 (m, 2H), 2.79-2.83 (m,4H), 1.87-1.81 (m, 2H). Mass Spectrum (LCMS, ESI) calculated forC₂₈H₂₈N₄O₃ 467.2 (M+H); found 467.3.

EXAMPLE 263-(4-cyano-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 4-Trimethylsilanylethynyl-benzonitrile

The title compound was synthesized from 4-benzobenzonitrile using theprocedure described in Example 18, step (a), in 80% yield. ¹H NMR(CDCl₃) *7.60-7.58 (m, 2H), 7.54-7.52 (m, 2H), 0.26 (s, 9H).

b) 4-Ethynyl-benzonitrile

The title compound was synthesized from4-trimethylsilanylethynyl-benzonitrile using the procedure described inExample 23, step (b), in 75% yield. ¹H NMR (CDCl₃) *7.64-7.61 (m, 2H),7.59-7.56 (m, 2H), 3.30 (s, 1H).

c) (4-Cyano-phenyl)-propynoic acid ethyl ester

The title compound was synthesized from 4-ethynyl-benzonitrile using theprocedure described in Example 23, step (c), in 59% yield. The crudeproduct was used in the next reaction without further purification.

d)7-(2-{1-[1-(4-Cyano-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (4-cyano-phenyl)-propynoic acidethyl ester using the procedure described in Example 16, step (c1), in78% yield as a mixture of E/Z isomers. ¹H NMR (CDCl₃) *7.74-7.64 (m,2H), 7.51 (d, 1H, J=8.3 Hz), 7.39-7.37 (m, 1H), 7.32 (d, 1H, J=7.6 Hz),7.12-7.09 (m, 1H), 7.05-7.03 (m, 1H), 6.94 (d, 1H, J=7.6 Hz), 6.84-6.65(m, 2H), 6.59 (d, 0.6H, J=3.3 Hz), 6.52 (d, 0.4H, J=3.5 Hz), 6.27 (s,0.6H), 6.23 (s, 0.4H), 4.40-4.35 (m, 2H), 4.11 (q, 0.8H, J=7.1 Hz), 4.03(q, 1.2H, J=7.1 Hz), 3.76 (t, 2H, J=6.0 Hz), 3.20 (t, 2H, J=6.9 Hz),2.73 (t, 2H, J=6.7 Hz), 1.93 (p, 2H, J=6.6 Hz), 1.52 (s, 9H), 1.20 (t,1.2H, J=7.1 Hz), 1.04 (t, 1.8H, J=7.1 Hz).

e)3-(4-Cyano-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester

The title compound was synthesized from7-(2-{1-[1-(4-cyano-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 45% yield. ¹H NMR (CDCl₃) *7.58-7.55 (m, 2H), 7.37 (d, 1H, J=3.2Hz), 7.32-7.29 (m, 1H), 7.26-7.11 (m, 2H), 7.03 (d, 1H, J=2.3 Hz),6.73-6.69 (m, 1H), 6.46-6.43 (m, 2H), 6.09-6.05 (m, 1H), 4.19 (t, 2H,J=6.8 Hz), 3.56 (s, 3H), 3.41-3.33 (m, 4H), 2.94 (t, 2H, J=7.0 Hz), 2.66(t, 2H, J=6.2 Hz), 1.83 (p, 2H, J=6.3 Hz). Mass Spectrum (LCMS, ESI)calculated for C₂₉H₂₉N₄O₃ 481.2 (M+H); found 481.4.

f)3-(4-Cyano-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-(4-cyano-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester using the procedure described in Example 18, step (g),in 43% yield. ¹H NMR (CDCl₃) *10.38 (s, 1H), 7.52-7.44 (m, 3H),7.20-7.10 (m, 4H), 6.87 (s, 1H, J=2.3 Hz), 6.62 (dd, 1H, J=2.3, 8.9 Hz),6.48 (d, 1H, J=3.1 Hz), 6.30 (d, 1H, J=7.3 Hz), 6.14 (dd, 1H, J=5.1,10.2 Hz), 3.75-3.70 (m, 1H), 3.60-3.55 (m, 1H), 3.39 (bt, 2H, J=5.1 Hz),3.28-3.12 (m, 2H), 2.74-2.58 (m, 4H), 1.87-1.82 (m, 2H). Mass Spectrum(LCMS, ESI) calculated for C₂₈H₂₇N₄O₃ 467.2 (M+H); found 467.3.

EXAMPLE 273-(2-Methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) (2-Methoxy-phenylethynyl)-trimethyl-silane

The title compound was synthesized from commercially available1-iodo-2-methoxy-benzene using the procedure described in Example 18,step (a), in 98% yield. ¹H NMR (CDCl₃) δ 7.60 (dd, 1H, J=1.8, 5.8 Hz),7.43 (m, 1H), 7.04 (m, 2H), 4.03 (s, 3H), 0.34 (s, 9H).

b) 2-Methoxy-phenylethynyl

The title compound was synthesized from(2-methoxy-phenylethynyl)-trimethyl-silane using the procedure describedin Example 18, step (b), in 63% yield. ¹H NMR (CDCl₃) δ 7.46 (dd, 1H,J=1.6, 6.0 Hz), 7.30 (m, 1H), 6.90 (m, 2H), 3.89 (s, 3H), 3.30 (s, 1H).

c) (2-Methoxy-phenyl)-propynoic acid ethyl ester

The title compound was synthesized from 2-methoxy-phenylethynyl usingthe procedure described in Example 23, step (c), in 71% yield. ¹H NMR(CDCl₃) δ 7.27 (m, 1H), 7.16 (m, 1H), 7.09 (m, 1H), 6.98 (m, 1H), 4.28(q, 2H, J=7.2 Hz), 3.79 (s, 3H), 1.25 (t, 3H, J=7.2 Hz).

d)7-(2-{1-[2-Ethoxycarbonyl-1-(2-methoxy-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (2-methoxy-phenyl)-propynoicacid ethyl ester and7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(d1), in a 80% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) [E/Zmixture] δ 7.45 (m, 1H), 7.28-6.95 (m, 4H), 6.85-6.60 (m, 4H), 6.49 (m,2H), 6.25 (s, 1H), 4.39 (m, 2H), 4.09 (q, 2H, J=7.2 Hz), 3.68 (s, 2H),3.58 (s, 1H), 3.80 (m, 2H), 3.20 (m, 2H), 2.70 (m, 2H), 1.89 (m, 2H),1.50 (s, 9H), 1.25 (t, 3H, J=6.8 Hz). Mass Spectrum (LCMS, ESI)calculated for C₃₀H₃₂N₃O₄ 498.2 (M-Boc+H); found 498.4.

e)7-(2-{1-[2-Ethoxycarbonyl-1-(2-methoxy-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(2-methoxy-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 44% yield. ¹H NMR (CDCl₃) δ 7.34-7.21 (m, 4H), 7.14 (m, 2H),6.99-6.80 (m, 4H), 6.45 (m, 1H), 6.36 (m, 1H), 4.37 (m, 2H), 4.04 (q,2H, J=7.1 Hz), 3.87 (s, 3H), 3.78 (m, 2H), 3.23 (m, 4H), 2.74 (m, 2H),1.94 (m, 2H), 1.54 (s, 9H), 1.08 (t, 3H, J=7.1 Hz).

f)3-(2-Methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(2-methoxy-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 84% yield. ¹H NMR (CDCl₃) δ 7.25-7.18 (m, 3H), 7.10 (m, 2H),6.90-6.81 (m, 4H), 6.44 (m, 2H), 6.38 (m, 1H), 5.10 (bs, 1H), 4.25 (m,2H), 4.11 (q, 2H, J=7.2 Hz), 3.84 (s, 3H), 3.41 (m, 2H), 3.24 (m, 2H),3.22 (m, 2H), 2.65 (m, 2H), 1.89 (m, 2H), 1.21 (t, 3H, J=7.2 Hz).

g)3-(2-Methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-(2-methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 14% yield. ¹H NMR (CDCl₃/CD₃OD) δ 7.57 (m, 1H), 7.27-7.14 (m, 3H),6.90 (d, 1H, J=8.4 Hz), 6.80 (m, 3H), 6.60 (dd, 1H, J=2.4, 6.4 Hz), 6.46(m, 2H), 6.29 (d, 1H, J=7.6 Hz), 3.93 (s, 3H), 3.54 (m, 2H), 3.45 (m,2H), 3.36-3.12 (m, 4H), 2.66 (m, 2H), 1.86 (m, 2H); Mass Spectrum (LCMS,ESI) calculated for C₂₈H₃₀N₃O₄ 472.2 (M+H); found 472.3.

EXAMPLE 283-(3-Methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) (3-Methoxy-phenylethynyl)-trimethyl-silane

The title compound was synthesized from commercially available1-iodo-3-methoxy-benzene using the procedure described in Example 18,step (a), in 98% yield. ¹H NMR (CDCl₃) δ 7.23 (t, 1H, J=7.8 Hz), 7.08(dt, 1H, J=1.2, 7.6 Hz), 7.02 (m, 1H), 6.89 (m, 1H), 3.82 (s, 3H), 0.28(s, 9H).

b) 3-Methoxy-phenylethynyl

The title compound was synthesized from(3-methoxy-phenylethynyl)-trimethyl-silane using the procedure describedin Example 18, step (b), in 74% yield. ¹H NMR (CDCl₃) δ 7.25 (t, 1H,J=7.9 Hz), 7.12 (d, 1H, J=1.0 Hz), 7.04 (m, 1H), 6.93 (m, 1H), 3.82 (s,3H), 3.09 (s, 1H).

c) (3-Methoxy-phenyl)-propynoic acid ethyl ester

The title compound was synthesized from 3-methoxy-phenylethynyl usingthe procedure described in Example 23, step (c), in 87% yield. ¹H NMR(CDCl₃) δ 7.26 (t, 1H, J=8.0 Hz), 7.18 (m, 1H), 7.08 (m, 1H), 6.98 (m,1H), 4.30 (q, 2H, J=7.2 Hz), 3.79 (s, 3H), 1.35 (t, 3H, J=7.2 Hz).

d)7-(2-{1-[2-Ethoxycarbonyl-1-(3-methoxy-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (3-methoxy-phenyl)-propynoicacid ethyl ester and7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(d1), in a 90% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) [E/Zmixture] δ 7.45-6.68 (m, 9H), 6.49 (m, 2H), 6.23 (s, 1H), 4.37 (m, 2H),4.13 (q, 2H, J=7.2 Hz), 3.76 (t, 2H, J=5.2 Hz), 3.68 (s, 2.1H), 3.58 (s,0.9H), 3.20 (m, 2H), 2.73 (t, 2H, J=6.8 Hz), 1.90 (m, 2H), 1.51 (s, 9H),1.26 (t, 2.1H, J=7.2 Hz), 1.13 (t, 0.9H, J=7.2 Hz). Mass Spectrum (LCMS,ESI) calculated for C₃₀H₃₂N₃O₄ 498.2 (M-Boc+1); found 498.4.

e)7-(2-{1-[2-Ethoxycarbonyl-1-(3-methoxy-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(3-methoxy-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 38% yield. ¹H NMR (CDCl₃) δ 7.32 (d, 1H, J=7.6 Hz), 7.22 (m,3H), 7.10 (d, 1H, J=2.4 Hz), 6.96 (d, 1H, J=7.6 Hz), 6.80 (m, 3H), 6.71(m, 1H), 6.45 (d, 1H, J=3.2 Hz), 5.99 (t, 1H, J=7.5 Hz), 4.38 (t, 2H,J=9.6 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.77 (m, 2H), 3.74 (s, 3H), 3.33-3.20(m, 4H), 2.75 (t, 2H, J=6.6 Hz), 1.93 (m, 2H), 1.53 (s, 9H), 1.12 (t,3H, J=7.1 Hz). Mass Spectrum (LCMS, ESI) calculated for C₃₀H₃₄N₃O₄ 500.3(M-Boc+1); found 500.4.

f)3-(3-Methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(3-methoxy-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 78% yield. ¹H NMR (CDCl₃) δ 7.21 (m, 3H), 7.05 (m, 2H), 6.80 (m,4H), 6.45 (m, 2H), 6.00 (t, 1H, J=8.0 Hz), 4.86 (bs, 1H), 4.30 (t, 2H,J=8.0 Hz), 4.05 (q, 2H, J=8.0 Hz), 3.80 (s, 3H), 3.43 (m, 2H), 3.27 (m,2H), 3.08 (m, 2H), 2.72 (m, 2H), 1.94 (m, 2H), 1.10 (t, 3H, J=8.0 Hz).

g)3-(3-Methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-(3-methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 22% yield. ¹H NMR (CDCl₃) δ 10.5 (bs, 1H), 7.50 (d, 1H, J=3.2 Hz),7.26 (m, 1H), 7.15 (m, 1H), 7.07 (m, 1H), 6.82 (d, 1H, J=2.3 Hz), 6.72(m, 3H), 6.60 (dd, 1H, J=2.3, 6.5 Hz), 6.46 (dd, 1H, J=3.0 Hz), 6.24 (d,1H, J=7.3 Hz), 6.09 (m, 1H), 3.70 (s, 3H), 3.57 (m, 1H), 3.46-3.15 (m,6H), 2.59 (m, 3H), 2.446 (m, 1H), 1.81 (m, 2H). Mass Spectrum (LCMS,ESI) calculated for C₂₈H₃₀N₃O₄ 472.2 (M+H); found 472.3.

EXAMPLE 293-(4-Methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) (4-Methoxy-phenylethynyl)-trimethyl-silane

The title compound was synthesized from commercially available1-iodo-4-methoxy-benzene using the procedure described in Example 18,step (a), in 95% yield. ¹H NMR (CDCl₃) δ 7.43 (d, 2H, J=4.6 Hz), 6.83(d, 2H, J=4.6 Hz), 3.82 (s, 3H), 0.26 (s, 9H).

b) 4-Methoxy-phenylethynyl

The title compound was synthesized from(4-methoxy-phenylethynyl)-trimethyl-silane using the procedure describedin Example 18, step (b), in 88% yield. ¹H NMR (CDCl₃) δ 7.46 (d, 2H,J=4.9 Hz), 6.87 (d, 2H, J=4.9 Hz), 3.83 (s, 3H), 3.02 (s, 1H).

c) (4-Methoxy-phenyl)-propynoic acid ethyl ester

The title compound was synthesized from 4-methoxy-phenylethynyl usingthe procedure described in Example 23, step (c), in 69% yield. ¹H NMR(CDCl₃) δ 7.53 (d, 2H, J=8.8 Hz), 6.87 (d, 2H, J=8.8 Hz), 4.28 (q, 2H,J=7.2 Hz), 3.82 (s, 3H), 1.34 (t, 3H, J=7.2 Hz).

d)7-(2-{1-[2-Ethoxycarbonyl-1-(4-methoxy-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (4-methoxy-phenyl)-propynoicacid ethyl ester and7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(d1), in a 88% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) [E/Zmixture] δ 7.32 (m, 2H), 7.21 (m, 1H), 7.11-6.85 (m, 6H), 6.70 (m, 1H),6.50 (m, 1H), 6.13 (s, 0.5H), 6.03 (s, 0.5H), 4.40 (m, 2H), 4.10 (q, 2H,J=7.2 Hz), 3.86 (s, 1.5H), 3.83 (s, 1H), 3.76 (t, 2H, J=5.2 Hz), 3.70(t, 2H, J=6.0 Hz), 3.20 (t, 2H, J=6.8 Hz), 2.70 (t, 2H, J=6.8 Hz, J=6.8Hz), 1.90 (m, 2H), 1.49 (s, 9H), 1.23 (t, 1.5H, J=7.2 Hz), 1.18 (t,1.5H, J=7.2 Hz). Mass Spectrum (LCMS, ESI) calculated for C₃₀H₃₂N₃O₄498.2 (M-Boc+H); found 498.4.

e)7-(2-{1-[2-Ethoxycarbonyl-1-(4-methoxy-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(4-methoxy-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 37% yield. ¹H NMR (CDCl₃) δ 7.24-7.00 (m, 6H), 6.87-6.73 (m,4H), 6.33 (d, 1H, J=2.8 Hz), 5.89 (m, 1H), 4.28 (t, 2H, J=6.8 Hz), 3.96(q, 2H, J=7.2 Hz), 3.68 (m, 5H), 3.16 (m, 4H), 2.73 (m, 2H), 1.85 (m,2H), 1.44 (s, 9H), 1.02 (t, 3H, J=7.2 Hz).

f)3-(4-Methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(4-methoxy-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 80% yield. ¹H NMR (CDCl₃) δ 7.28-7.08 (m, 6H), 6.83 (m, 4H),6.43 (d, 1H, J=2.8 Hz), 5.97 (m, 1H), 4.89 (bs, 1H), 4.28 (m, 2H), 4.05(q, 2H, J=7.2 Hz), 3.77 (s, 3H), 3.41 (m, 2H), 3.26 (m, 2H), 3.04 (m,2H), 2.66 (m, 2H), 1.91 (m, 2H), 1.11 (t, 3H, J=7.2 Hz).

g)3-(4-Methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-(4-methoxy-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 15% yield. ¹H NMR (CDCl₃) δ 10.6 (bs, 1H), 7.47 (d, 1H, J=3.2 Hz),7.28 (d, 1H, J=8.9 Hz), 7.08 (m, 3H), 6.84 (d, 1H, J=2.3 Hz), 6.76 (d,2H, J=8.8 Hz), 6.61 (dd, 1H, J=2.4, 6.5 Hz), 6.46 (m, 1H), 6.25 (d, 1H,J=7.3 Hz), 6.08 (m, 1H), 3.73 (s, 3H), 3.59 (m, 1H), 3.40 (m, 3H),3.29-3.13 (m, 2H), 2.60 (m, 4H), 2.46 (m, 1H), 1.85 (m, 2H). MassSpectrum (LCMS, ESI) calculated for C₂₈H₃₀N₃O₄ 472.2 (M-Boc+H); found472.3.

EXAMPLE 303-Quinolin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 3-Ethynyl-quinoline

The title compound was synthesized from 3-bromoquinoline using theprocedures described in Example 18, step (a) and step (b), in 68% yield.¹H NMR Cl₃CD, δ: 3.28 (s, 1H), 7.60 (m, 1H), 7.74 (m, 1H), 7.80 (m, 1H),8.09 (d, 1H, J=8.8 Hz), 8.29 (d, 1H, J=2.0 Hz), 8.95 (d, 1H, J=2.0 Hz).

b) Quinolin-3-yl-propynoic acid ethyl ester

The title compound was synthesized from 3-ethynyl-quinoline using theprocedure described in Example 23, step (c), in 34% yield. ¹H NMR Cl₃CD,δ: 1.38 (t, 3H, J=7.2 Hz), 4.34 (c, 2H, J=7.2 Hz), 7.60 (m, 1H), 7.80(m, 2H), 8.11 (d, 1H, J=8.4 Hz), 8.40 (d, 1H, J=2.0 Hz), 8.99 (d, 1H,J=2.0 Hz).

c)7-{2-[1-2-Ethoxycarbonyl-1-quinolin-3-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from quinolin-3-yl-propynoic acidethyl ester and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(d1), in 81% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) δ 8.90 (m,1H), 8.14 (m, 1.3H), 8.04 (m, 0.7H), 7.79 (m, 2H), 7.58 (m, 1H), 7.30(d, 1H, J=7.6 Hz), 7.13(m, 2H), 6.93 (m, 1.3H), 6.75 (m, 1.7H), 6.63 (d,0.7H, J=3.2 Hz), 6.53 (d, 0.3H, J=3.2 Hz), 6.38 (s, 0.7H), 6.32 (s,0.3H), 4.38 (m, 2H), 4.05 (m, 2H), 3.75 (t, 2H, J=6.4 Hz), 3.19 (t, 2H,J=6.4 Hz), 2.72 (t, 2H, J=6.4 Hz), 1.91 (m, 2H), 1.51 (s, 9H), 1.13 (t,0.9H, J=7.0 Hz), 1.05 (t, 2.1H, J=7.0 Hz).

d)7-{2-[1-(2-Ethoxycarbonyl-1-quinolin-3-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-2-ethoxycarbonyl-1-quinolin-3-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 17% yield. ¹H NMR (CDCl₃) δ 8.81 (d, 1H, J=4.4 Hz), 8.07 (d, 1H,J=2.1 Hz), 7.88 (d, 1H, J=2.4 Hz), 7.10 (m, 2H), 7.54 (m, 1H), 7.25 (m,3H), 7.11 (d, 1H, J=2.0 Hz), 6.94 (d, 1H, J=7.6 Hz), 6.82 (dd, 1H,J=2.4, 6.4 Hz), 6.50 (d, 1H, J=3.2 Hz), 6.24 (t, 1H, J=7.6 Hz), 4.37 (t,2H J=6.8 Hz), 4.10 (m, 2H), 3.76 (m, 2H), 3.40 (t, 2H, J=7.6 Hz), 3.20(t, 2H, J=6.8 Hz), 2.73 (t, 2H, J=6.8 Hz), 1.92 (m, 2H), 1.51 (s, 9H),1.13 (t, 3H, J=6.8 Hz).

e)3-Quinolin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-quinolin-3-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 60% yield. ¹H NMR (CDCl₃) δ 8.83 (d, 1H, J=2.0 Hz), 8.08 (d, 1H,J=8.8 Hz), 7.88 (d, 1H, J=2.0 Hz), 7.71 (m, 2H), 7.54 (m, 1H), 7.23 (m,2H), 7.10 (m, 2H), 6.84 (dd, 1H, J=2.4, 6.4 Hz), 6.49 (m, 2H), 6.24 (t,1H, J=3.2 Hz), 4.95 (s, 1H), 4.29 (t, 2H, J=6.8 Hz), 4.08 (m, 2H), 3.41(m, 4H), 3.05 (t, 2H, J=6.4 Hz), 2.70 (t, 2H, J=6.0 Hz), 1.92 (m, 2H),1.13 (t, 3H, J=7.2 Hz).

f)3-Quinolin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-quinolin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 21% yield. ¹H NMR (CDCl₃) δ 10.21 (bs, 1H), 8.87 (d, 1H, J=2.4 Hz),8.04 (d, 1H, J=8.8 Hz), 7.78 (d, 1H, J=1.6 Hz), 7.67 (m, 2H), 7.50 (m,2H), 7.13 (d, 2H, J=7.6 Hz), 6.91 (d, 1H, J=2.4 Hz), 6.54 (dd, 1H,J=0.8, 8.8 Hz), 6.52 (d, 1H, J=2.8 Hz), 6.30 (m, 2H), 3.71 (m, 2H), 3.37(m, 4H), 2.65 (m, 4H), 1.82 (m, 2H). Mass Spectrum (LCMS, ESI)calculated for C₃₀H₂₉N₄O₃: 493.2 (M+H), found: 493.3.

EXAMPLE 313-(3-Chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) (3-Chloro-phenylethynyl)-trimethyl-silane

The title compound was synthesized from commercially available1-iodo-3-chloro-benzene using the procedure described in Example 18,step (a), in 98% yield. ¹H NMR (CDCl₃) δ 7.48 (t, 1H, J=1.8 Hz), 7.36(dt, 1H, J=1.4, 7.5 Hz), 7.30 (m, 1H), 7.26 (m, 1H), 0.28 (s, 9H).

b) 3-Chloro-phenylethynyl

The title compound was synthesized from(3-chloro-phenylethynyl)-trimethyl-silane using the procedure describedin Example 23, step (b), in 98% yield. ¹H NMR (CDCl₃) δ 7.48 (m, 1H),7.38 (m, 2H), 7.25 (m, 1H), 3.11 (s, 1H).

c) (3-Chloro-phenyl)-propynoic acid ethyl ester

The title compound was synthesized from 4-chloro-phenylethynyl using theprocedure described in Example 23, step (c), in 52% yield. ¹H NMR(CDCl₃) δ 7.61 (m, 1H), 7.41 (m, 2H), 7.25 (m, 1H), 4.32 (q, 2H), 1.31(t, 3H).

d)7-(2-{1-[1-(3-Chloro-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (3-chloro-phenyl)-propynoic acidethyl ester and7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(d1), in 90% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) [E/Zmixture] δ 7.36-7.24 (m, 2H), 7.14-7.6.70 (m, 8H), 6.56 (s, 0.5H), 6.48(m, 0.5H), 6.21 (s, 0.5H), 6.14 (s, 0.5H), 4.37 (m, 2H), 4.12 (q, 2H,J=6.8 Hz), 3.76 (m, 2H), 3.20 (t, 2H, J=6.8 Hz), 2.73 (t, 2H, J=6.8 Hz),1.92 (m, 2H), 1.52 (s, 9H), 1.26 (t, 3H, J=7.2 Hz). Mass Spectrum (LCMS,ESI) calculated for C₂₉H₂₉ClN₃O₃ 502.2 (M-Boc+1); found 502.4.

e)7-(2-{1-[1-(3-Chloro-phenyl)-2-ethoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[1-(3-chloro-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 86% yield. ¹H NMR (CDCl₃) δ 7.23-7.01 (m, 7H), 6.94 (m, 1H),6.85 (d, 1H, J=7.6 Hz), 6.75 (dd, 1H, J=2.4, 6.5 Hz), 6.37 (d, 1H, J=4.0Hz), 5.89 (t, 1H, J=7.5 Hz), 4.28 (q, 2H, J=6.9 Hz), 3.98 (q, 2H, J=7.1Hz), 3.67 (m, 2H), 3.14 (m, 4H), 2.64 (t, 2H, J=6.6 Hz), 1.83 (m, 2H),1.43 (s, 9H), 1.02 (t, 3H, J=7.1 Hz). Mass Spectrum (LCMS, ESI)calculated for C₂₉H₃₁ClN₃O₃ 504.2 (M-Boc+H); found 504.4.

f)3-(3-Chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-(2-{1-[1-(3-Chloro-phenyl)-2-ethoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 63% yield. ¹H NMR (CDCl₃) δ 7.26-7.00 (m, 8H), 6.82 (dd, 1H,J=2.4, 6.4 Hz), 6.46 (m, 1H), 5.97 (t, 1H, J=7.6 Hz), 4.85 (bs, 1H),4.30 (t, 2H, J=7.2 Hz), 4.06 (q, 2H, J=7.2 Hz), 3.39 (m, 2H), 3.31-3.18(m, 2H), 3.03 (t, 1H, J=6.8 Hz), 2.68 (t, 2H, J=6.4 Hz), 1.89 (m, 2H),1.10 (t, 3H, J=7.2 Hz).

g)3-(3-Chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-(3-chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 30% yield. ¹H NMR (CDCl₃/CD₃OD) δ 7.24 (d, 1H, J=3.2 Hz), 7.13 (d,1H, J=7.3 Hz), 7.03 (m, 4H), 6.85 (m, 2H), 6.60 (m, 1H), 6.33 (m, 2H),5.85 (m, 1H), 3.30-3.21 (m, 4H), 3.00 (m, 2H), 2.81 (m, 2H), 2.57 (m,2H), 1.76 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C₂₇H₂₇ClN₃O476.2 (M+H); found 476.9.

EXAMPLE 323-Naphthalen-2-yl-3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 3-Naphthalen-2-yl-3-oxo-propionic acid ethyl ester

Diethylcarbonate (3.90 mL, 33.0 mmol) was added to a slurry of sodiumhydride (1.30 g, 33.0 mmol) in toluene (100 mL) at room temperatureunder Ar. A solution of 2-acetophenone (5.00 g, 29.0 mmol) in toluene(30 mL) was added immediately and the mixture was heated at reflux for 2hours. After cooling to room temperature, the mixture was poured overice/water and extracted with ethyl acetate. The organic extracts weredried over magnesium sulfate and the solvent was removed under reducedpressure. The crude product was purified over silica (2.5% ethylacetate/hexanes) to give the title compound (4.45 g, 55%, 3:1 mixture ofketo/enol form) as clear oil. ¹H NMR (CDCl₃) δ 12.69 (s, 0.25H, enol),8.46 (d, 0.75H, J=0.8 Hz), 8.37 (d, 0.25H, J=0.8 Hz), 7.98 (m, 2H),7.88(m, 3H), 7.78 (m, 0.25H), 7.57 (m, 2.75H), 5.82 (s, 0.25H, enol),4.27 (m, 2H), 4.13 (s, 1.5H, keto) 1.36 (t, 0.75H, J=8.0 Hz), 1.27 (t,1.25H, J=8.0 Hz).

b) Naphthalene-2-yl-propynoic acid ethyl ester

Triflic anhydride (2.9 mL, 17 mmol) was added dropwise to a solution oftriphenylphosphine oxide (4.8 g, 17 mmol) in 1,2-dichloroethane (40 mL)at 0° C. The resulting suspension was stirred for 15 minutes, followedby the dropwise addition of a solution of3-naphthalen-2-yl-3-oxo-propionic acid ethyl ester (3.2 g, 12 mmol) in1,2-dichloroethane (40 mL). After the addition was complete,triethylamine (4.0 mL, 29 mmol) was added and the reaction mixture washeated at reflux for 1 hr. The solution was cooled to room temperature,washed with water, and dried (MgSO₄). The solvent was removed underreduced pressure, and the product was purified via column chromatographywith silica eluting with hexane/ethyl acetate (9/1) to yieldnaphthalene-2-yl-propynoic acid ethyl ester (1.15 g, 37% yield) as ayellow oil. ¹H NMR (CDCl₃) δ 8.25 (s, 1H), 7.95 (m, 3H), 7.66 (m, 3H),4.46 (m, 2H), 1.51 (t, 3H, J=8.0 Hz).

c)7-{2-[1-(2-Ethoxycarbonyl-1-naphthalen-2-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from naphthalene-2-yl-propynoic acidethyl ester and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(d1), in 88% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) δ 7.85 (m,4H), 7.50 (m, 2.6H), 7.33 (m, 1.6H), 7.12 (m, 1.8H), 6.95 (m, 1.4H),6.74 (m, 1.6H), 6.61 (d, 0.6H, J=0.4 Hz), 6.50 (d, 0.4H, J=0.4 Hz), 6.35(s, 0.6H), 6.23 (s, 0.4 HZ), 4.36 (t, 2H, J=8.0 Hz), 4.05 (m, 2H), 3.76(m, 2H), 3.20 (t, 2H, J=8.0), 2.73 (t, 2H, J=8.0 Hz), 1.92 (m, 2H), 1.51(s, 9H), 1.07 (m, 3H).

d)7-{2-[1-(2-Ethoxycarbonyl-1-naphthalen-2-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-naphthalen-2-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 80% yield. ¹H NMR (CDCl₃) δ 7.76 (m, 3H), 7.67 (s, 1H), 7.45 (m,2H), 7.29 (d, 1H, J=7.6 Hz), 7.23 (m, 3H), 7.09 (d, 1H, J=2.4 Hz), 6.92(d, 2H, J=8.0 Hz), 6.80 (dd, 1H, J=2.4, 6.4 Hz), 6.18 (t, 1H, J=7.6 Hz),4.35 (t, 2H, J=7.2 Hz), 4.08 (m, 2H), 3.75 (m, 2H), 3.36 (m, 2H), 3.19(t, 2H, J=6.8 Hz), 2.71 (t, 2H, J=6.8 Hz), 1.91 (m, 2H), 1.50 (s, 9H),1.10 (t, 3H, J=6.8 Hz).

e)3-Naphthalen-2-yl-3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-naphthalen-2-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 71% yield. ¹H NMR (CDCl₃) δ 7.76 (m, 3H), 7.67 (s, 1H), 7.46 (m,2H), 7.23 (m, 3H), 7.08(m, 2H), 6.80 (dd, 1H, J=2.4, 6.4 Hz), 6.45 (m,2H), 6.17 (t, 1H, J=Hz), 5.07 (s, 1H), 4.27 (t, 2H, J=6.8 Hz), 4.05 (m,2H), 3.38 (m, 4H), 3.05 (t, 2H, J=6.8 Hz), 2.67 (t, 2H, J=6.4 Hz), 1.88(m, 2H), 1.09 (t, 3H, J=7.2 Hz).

f)3-Naphthalen-2-yl-3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-naphthalen-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 34% yield. ¹H NMR (DMSO-d₆) δ 7.90 (s, 1H), 7.84 (m, 3H), 7.71 (d,1H, J=3.2 Hz), 7.47 (m, 4H), 7.02 (m, 2H), 6.68 (dd, 1H, J=2.4, 6.4 Hz),6.39 (d, 1H, J=2.8 Hz), 6.34 (d, 1H, J=7.2 Hz), 6.31 (s, 1H), 6.10 (m,1H), 4.18 (t, 2H, J=6.8 Hz), 3.59 (m, 2H), 3.23 (m, 2H), 2.85 (t, 2H,J=6.8 Hz), 2.50 (t, 2H, J=2.0 Hz), 1.75 (m, 2H). Mass Spectrum (LCMS,ESI) calculated for C₃₁H₃₀N₃O₃: 492.2 (M+H), found: 492.3.

EXAMPLE 333-(2-Chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) (2-Chloro-phenyl)-propynoic acid methyl ester

The title compound was synthesized from commercially available3-(2-chloro-phenyl)-3-oxo-propionic acid methyl ester using theprocedure described in Example 32, step (b), in 71% yield. ¹H NMR(CDCl₃) δ 7.53 (dd, 1H, J=1.6, 6.0 Hz), 7.36 (m, 1H), 7.30 (dt, 1H,J=1.6, 5.7 Hz), 7.19 (dt, 1H, J=1.3, 6.4 Hz), 3.78 (s, 3H).

b)7-(2-{1-[1-(2-Chloro-phenyl)-2-methoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (2-chloro-phenyl)-propynoic acidmethyl ester and7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(d1), in 43% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) [E/Zmixture] δ 7.54-7.30 (m, 6H), 7.18 (m, 1H), 6.95 (m, 1H), 6.83 (m, 1H),6.68-6.50 (m, 2H), 6.35 (s, 0.33H), 5.95 (s, 0.67H), 4.39 (m, 2H), 3.78(m, 2H), 3.64 (s, 3H), 3.22 (m, 2H), 2.73 (m, 2H), 1.92 (m, 2H), 1.52(s, 9H). Mass Spectrum (LCMS, ESI) calculated for C₂₈H₂₇ClN₃O₃ 488.2(M-Boc+H); found 488.4.

c)7-(2-{1-[1-(2-Chloro-phenyl)-2-methoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[1-(2-chloro-phenyl)-2-methoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 85% yield. ¹H NMR (CDCl₃) δ 7.41-7.25 (m, 3H), 7.22-6.79 (m,7H), 6.50 (m, 1H), 6.40 (m, 1H), 4.37 (t, 2H, J=7.2 Hz), 3.76 (m, 2H),3.61 (s, 3H), 3.20 (m, 4H), 2.75 (m, 2H), 1.94 (m, 2H), 1.50 (s, 9H).

d)3-(2-Chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester

The title compound was synthesized from7-(2-{1-[1-(2-chloro-phenyl)-2-methoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 45% yield. ¹H NMR (CDCl₃) δ 7.31 (m, 1H), 7.20-7.00 (m, 6H),6.83 (dd, 1H, J=1.7, 6.0 Hz), 6.74 (dd, 1H, J=1.7, 6.0 Hz), 6.39 (m,2H), 6.32 (m, 1H), 4.82 (s, 1H), 4.21 (m, 2H), 3.54 (s, 3H), 3.32 (m,2H), 3.17 (m, 2H), 2.95 (m, 2H), 2.62 (m, 2H), 1.82 (m, 2H).

e)3-(2-Chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-(2-chloro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester using the procedure described in Example 18, step (g),in 33% yield. ¹H NMR (CDCl₃) δ 10.4 (bs, 1H), 7.60 (d, 1H, J=2.8 Hz),7.37 (dd, 1H, J=1.2, 6.8 Hz), 7.18-7.04 (m, 4H), 6.85 (dd, 1H, J=1.4,6.3 Hz), 6.78 (d, 1H, J=2.3 Hz), 6.59 (dd, 1H, J=2.2, 6.7 Hz), 6.49 (m,2H), 6.23 (d, 1H, J=7.2 Hz), 3.42 (m, 3H), 3.39-3.08 (m, 4H), 2.62 (t,2H, J=6.2 Hz), 2.51 (m, 1H), 3.35 (m, 1H), 1.82 (m, 2H). Mass Spectrum(LCMS, ESI) calculated for C₂₇H₂₇ClN₃O₃ 476.2 (M+H); found: 476.31.

EXAMPLE 343-Naphthalen-1-yl-3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 3-Naphthalen-1-yl-3-oxo-propionic acid ethyl ester

The title compound was synthesized from commercially available1-acetonapthrone using the procedure described in Example 32, step (a),in 25% yield as a 3:1 mixture of keto/enol tautomers. ¹H NMR (CDCl₃) δ12.73 (s, 0.25H, enol), 8.75 (dd, 0.75H, J=4.0, 8.0 Hz, keto), 8.36 (dd,0.25H, J=4.0, 8.0 Hz, enol), 8.03 (d, 0.75H, J=8.0 Hz), 7.90 (m, 2.75H),7.64 (m, 1.5H), 7.54 (m, 3H), 5.50 (s, 0.25H, enol), 4.32 (m, 0.5H),4.20 (m, 1.5H) 4.11 (s, 1.5H, keto), 1.36 (t, 0.75H, J=8.0 Hz), 1.21 (t,1.25, J=8.0 Hz).

b) Naphthalene-1-yl-propynoic acid ethyl ester

The title compound was synthesized from3-naphthalen-1-yl-3-oxo-propionic acid ethyl ester using the proceduredescribed in Example 32, step (b), in 25% yield. ¹H NMR (CDCl₃) δ 8.35(dd, 1H, J=0.4, 1.4 Hz), 7.95 (d, 1H, J=8.0 Hz), 7.86 (m, 2H), 7.61 (m,2H), 7.46(m, 1H), 4.36 (m, 2H), 1.41 (t, 3H, J=8.0 Hz).

c)7-{2-[1-(2-Ethoxycarbonyl-1-naphthalen-1-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from naphthalene-1-yl-propynoic acidethyl ester and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(d1), in 37% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) δ 8.32 (m,1H), 7.85 (m, 2H), 7.47 (m, 3H), 7.27 (m, 2.5H), 6.95 (m, 3H), 6.72 (m,1.5H), 6.58 (m, 0.5H), 6.35 (m, 1.5H), 4.27 (m, 2H), 4.03 (m, 2H), 3.69(m, 2H), 3.14 (m, 2H), 2.67 (m, 2H), 1.86 (m, 2H), 1.45 (s, 9H), 1.18(m, 3H).

d)7-{2-[1-(2-Ethoxycarbonyl-1-naphthalen-1-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-naphthalen-1-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 23% yield. ¹H NMR (CDCl₃) δ 8.04 (m, 1H), 7.88 (m, 1H), 7.81 (d,1H, J=8.4 Hz), 7.50 (m, 2H), 7.40 (t, 1H, J=7.6 Hz), 7.28 (m, 4H), 7.10(d, 1H, J=2.4 Hz), 6.96 (t, 1H, J=7.6 Hz), 6.83 (m, 2H), 6.40 (d, 1H,J=8.0 Hz), 4.35 (t, 2H, J=8.0 Hz), 4.06 (m, 2H), 3.77 (m, 2H), 3.36 (m,2H), 3.21 (t, 2H, J=8.0 Hz), 2.74(t, 2H, J=8.0 Hz), 1.92 (m, 2H), 1.50,(s, 9H), 1.11 (t, 3H, J=8.0 Hz).

e)3-Naphthalen-1-yl-3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-naphthalen-1-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 90% yield. ¹H NMR (CDCl₃) δ 8.02 (m, 1H), 7.89 (m, 1H), 7.81 (d,1H, J=8.0 Hz), 7.50 (m, 2H), 7.39 (t, 1H, J=7.6 Hz), 7.28(m, 2H), 7.10(m, 3H), 6.85 (m, 2H), 6.48 (m, 1H), 6.41 (d, 1H, J=3.2 Hz), 4.92 (s,1H), 4.30 (t, 2H, J=7.2 Hz), 4.07 (m, 2H), 3.37 (m, 4H), 3.05 (t, 2H,J=6.4 Hz), 2.68 (t, 2H, J=6.4 Hz), 1.88 (m, 2H), 1.09 (t, 3H, J=7.2 Hz).

f)3-Naphthalen-1-yl-3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-naphthalen-1-yl-3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 52% yield. ¹H NMR (DMSO-d₆) δ 8.17 (d, 1H, J=8.4 Hz), 7.96 (m, 1H),7.88 (d, 1H, J=8.0 Hz), 7.55 (m, 3H), 7.45(t, 1H, J=7.2 Hz), 7.30 (m,2H), 7.03 (m, 2H), 6.68 (m, 2H), 6.36 (m, 2H), 6.31 (s, 1H), 4.19 (t,2H, J=7.2 Hz), 3.60 (m, 2H) 3.24 (m, 2H), 2.86 (t, 2H, J=7.2 Hz), 2.60(t, 2H, J=6.4 Hz), 1.74 (m, 2H). Mass Spectrum (LCMS, ESI) calculatedfor C₃₁H₃₀N₃O₃: 492.2 (M+H), found: 492.3.

EXAMPLE 353-(4-Fluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) (4-Fluoro-phenyl)-propynoic acid methyl ester

The title compound was synthesized from3-(4-fluoro-phenyl)-3-oxo-propionic acid methyl ester using theprocedure described in Example 32, step (b), in 91% yield. ¹H NMR(CDCl₃) δ 7.59 (m, 2H), 7.08 (m, 2H), 3.84 (s, 3H).

b)7-(2-{1-[1-(4-Fluoro-phenyl)-2-methoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from (4-fluoro-phenyl)-propynoic acidmethyl ester and7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 17, step(a), in 73% yield as an E/Z isomeric mixture. ¹H NMR (CDCl₃) [E/Zmixture] δ 7.43 (m, 1H), 7.30 (m, 2H), 7.00-7.20 (m, 3), 6.94 (m, 1H),6.50-6.90 (m, 3H), 6.12 (s, 1H), 4.36 (m, 2H), 3.75 (m, 2H), 3.7 and 3.6(s, 3H), 3.20 (m, 2H), 2.75 (m, 2H), 1.90 (m, 2H), 1.50 (s, 9H). MassSpectrum (LCMS, ESI) calculated for C₃₃H₃₅FN₃O₅ 572.3 (M+H); found 472.3(M-Boc+H).

c)7-(2-{1-[1-(4-Fluoro-phenyl)-2-methoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[1-(4-fluoro-phenyl)-2-methoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 57% yield. ¹H NMR (CDCl₃) δ 7.34 (d, 1H), 7.15 (m, 4H), 6.95 (m,4H), 6.80 (d, 1H), 6.45 (d, 1H), 6.00 (t, 1H), 4.40 (t, 2H), 7.50 (t,2H), 3.60 (s, 3H), 3.15-3.30 (m, 4H), 2.72 (t, 2H), 1.90 (m, 2H), 1.50(s, 9H). Mass Spectrum (LCMS, ESI) calculated for C₃₃H₃₇FN₃O₅ 574.3(M+H); found 474.2 (M-Boc+H).

d)3-(4-Fluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester

The title compound was synthesized from7-(2-{1-[1-(4-fluoro-phenyl)-2-methoxycarbonyl-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 83% yield. ¹H NMR (CDCl₃) δ 7.04 (m, 4H), 6.86 (m, 2H), 6.87 (t,2H), 6.75 (dd, J=2.4 and 8.9 Hz, 1H), 6.36 (m, 2H), 5.90 (t, 1H), 4.91(br, 1H), 4.20 (t, J=7.0 Hz, 2H), 3.53 (s, 3H), 3.30 (m, 2H), 3.20 (m,2H), 2.95 (t, J=7.0 Hz, 2H), 2.60 (t, 2H), 1.82 (m, 2H). Mass Spectrum(LCMS, ESI) calculated for C₂₈H₂₉FN₃O₃ 474.2 (M+H); found 474.3.

e)3-(4-Fluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-(4-fluoro-phenyl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester using the procedure described in Example 16, step (g),in 64% yield. ¹H NMR (CDCl₃) δ 10.47 (br, 1H), 10.39 (d, J=3.2 Hz, 1H),7.15 (d, J=8.9 Hz, 1H), 7.04 (m, 3H), 6.83 (m, 3H), 6.54 (q, 1H), 6.39(d, J=3.0 Hz, 1H), 6.20 (d, J=7.2 Hz), 6.02 (q, 1H), 3.57 (br, 1H), 3.40(br, 1H), 3.31 (t, J=5.3 Hz, 2H), 3.05-3.18 (m, 2H), 2.43-2.58 (m, 4H),1.76 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C₂₇H₂₇FN₃O₃ 460.2(M+H); found 460.2.

EXAMPLE 363-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(3-trifluoromethyl-phenyl)-propionicacid

a) (3-Trifluoromethyl-phenyl)-propynoic acid methyl ester

The title compound was synthesized from commercially available3-oxo-3-(3-trifluoromethyl-phenyl)-propionic acid methyl ester using theprocedure described in Example 32, step (b), in 100% yield. ¹H NMR(CDCl₃) δ 7.84 (s, 1H), 7.75 (q, 1H), 7.50 (t, 1H), 3.90 (s, 3H).

b)7-(2-{1-[2-Methoxycarbonyl-1-(3-trifluoromethyl-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from(3-trifluoromethyl-phenyl)-propynoic acid methyl ester using theprocedure described in Example 16, step (d2), in 47% yield. ¹H NMR(CDCl₃) δ 7.77 (m, 1H), 7.67 (s, 1H), 7.60 (m, 2H), 7.34 (d, J=7.7 Hz,1H), 7.13 (m, 2H), 6.96 (d, J=7.6 Hz, 1H), 6.85 (m, 2H), 6.54 (dd, J=3.5and 0.6 Hz, 1H), 6.26 (s, 1H), 4.41 (m, 2H), 3.78 (m, 2H), 3.67 (s, 3H),3.23 (t, J=6.8 Hz, 2H), 2.76 (t, J=6.7 Hz, 2H), 1.94 (m, 2H), 1.54 (s,9H). Mass Spectrum (LCMS, ESI) calculated for C₃₄H₃₅F₃N₃O₅ 622.3 (M+H);found: 522.4 (M-Boc+H).

c)7-(2-{1-[2-Methoxycarbonyl-1-(3-trifluoromethyl-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[2-methoxycarbonyl-1-(3-trifluoromethyl-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 70% yield. ¹H NMR (CDCl₃) δ 7.45 (m, 3H), 7.23 (m, 1H), 7.17 (m,1H), 7.10 (m, 1H), 7.06 (m, 1H), 6.87 (m, 1H), 6.75 (m, 1H), 6.40 (m,1H), 5.97 (t, J=7.5 Hz, 1H), 4.28 (m, 2H), 3.72 (m, 2H), 3.54 (s, 3H),3.07-3.29 (m, 4H), 2.66 (m, 2H), 1.84 (m, 2H), 1.45 (s, 9H). MassSpectrum (LCMS, ESI) calculated for C₃₄H₃₇F₃N₃O₅ 624.3 (M+H); found:524.4 (M-Boc+H).

d)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(3-trifluoromethyl-phenyl)-propionicacid methyl ester

The title compound was synthesized from7-(2-{1-[2-methoxycarbonyl-1-(3-trifluoromethyl-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 37% yield. ¹H NMR (CDCl₃) δ 7.43 (m, 2H), 7.32 (t, J=7.8 Hz,1H), 7.19 (m, 1H), 7.01-7.13 (m, 3H), 6.75 (dd, J=2.3 and 8.9 Hz, 1H),6.39 (m, 2H), 5.98 (m, 1H), 4.22 (m, 2H), 3.54 (s, 3H), 3.16-3.40 (m,4H), 2.96 (m, 2H), 2.62 (t, J=6.2 Hz, 2H), 1.82 (m, 2H). Mass Spectrum(LCMS, ESI) calculated for C₂₉H₂₉F₃N₃O₃ 524.2 (M+H); found 524.4.

e)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(3-trifluoromethyl-phenyl)-propionicacid

The title compound was synthesized from3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(3-trifluoromethyl-phenyl)-propionicacid methyl ester using the procedure described in Example 16, step (g),in 55% yield. ¹H NMR (CDCl₃) δ 10.5 (br, 1H), 7.48 (m, 3H), 7.35 (t,J=7.6 Hz, 1H), 7.25 (m, 3H), 7.15 (dd, J=7.0 and 8.5 Hz, 1H), 6.88 (d,J=2.2 Hz, 1H), 6.63 (dd, J=2.2 and 8.9 Hz, 1H), 6.50 (s, 1H), 6.30 (d,J=7.3 Hz, 1H), 6.18 (q, 1H), 3.73 (m, 1H), 3.55 (m, 1H), 3.40 (m, 2H),3.13-3.31 (m, 2H), 2.76 (m, 4H), 1.85 (m, 2H). Mass Spectrum (LCMS, ESI)calculated for C₂₈H₂₇F₃N₃O₃ 510.2 (M+H); found 510.3 (M⁺+1, 100%).

EXAMPLE 373-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(4-trifluoromethyl-phenyl)-propionicacid

a) (4-Trifluoromethyl-phenyl)-propynoic acid methyl ester

The title compound was synthesized from commercial available3-oxo-3-(4-trifluoromethyl-phenyl)-propionic acid methyl ester using theprocedure described in Example 32, step (b), in 84% yield. ¹H NMR(CDCl₃) δ 7.70 (m, 4H), 3.85 (s, 3H).

b)7-(2-{1-[2-Methoxycarbonyl-1-(4-trifluoromethyl-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from(4-trifluoromethyl-phenyl)-propynoic acid methyl ester using theprocedure described in Example 16, step (d2), in 62% yield as an E/Zisomeric mixture. ¹H NMR (CDCl₃) [E/Z mixture] δ 7.62 (d, J=8.1 Hz, 1H),7.54 (d, J=8.2 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.33 (m, 1H), 7.23 (m,1H), 7.05 (m, 2H), 6.88 (m, 1H), 6.75 (m, 1H), 6.53 (m, 1H), 6.17 (s,1H), 4.31 (m, 2H), 3.69 (m, 2H), 3.53 (s, 3H), 3.13 (m, 2H), 2.66 (t,J=6.6 Hz, 2H), 1.85 (m, 2H), 1.44 (s, 9H). Mass Spectrum (LCMS, ESI)calculated for C₃₄H₃₅F₃N₃O₅ 622.3 (M+H); found: 522.4 (M-Boc+H).

c)7-(2-{1-[2-Methoxycarbonyl-1-(4-trifluoromethyl-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[2-methoxycarbonyl-1-(4-trifluoromethyl-phenyl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 36% yield, and was used directly in the next reaction withoutpurification.

d)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(4-trifluoromethyl-phenyl)-propionicacid methyl ester

The title compound was synthesized from7-(2-{1-[2-methoxycarbonyl-1-(4-trifluoromethyl-phenyl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 33% yield. ¹H NMR (CDCl₃) δ 7.60 (d, 2H), 7.30 (d, 2H), 7.15 (d,1H), 7.10 (m, 3H), 6.83 (m, 1H), 6.50 (m, 2H), 6.08 (t, 1H), 5.15 (br,1H), 4.33 (t, 2H), 3.60 (s, 3H), 3.25-3.45 (m, 4H), 3.10 (m, 2H), 2.75(m, 2H), 1.90 (m, 2H). Mass Spectrum (LCMS, ESI) calculated forC₂₉H₂₉F₃N₃O₃ 524.2 (M+H); found: 524.4.

e)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(4-trifluoromethyl-phenyl)-propionicacid

The title compound was synthesized from3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-(4-trifluoromethyl-phenyl)-propionicacid methyl ester using the procedure described in Example 16, step (g),in 67% yield. ¹H NMR (CDCl₃) δ 10.60 (br, 1H), 7.40 (d, J=8.0 Hz, 3H),7.15 (d, J=8.1 Hz, 2H), 7.08 (m, 2H), 6.81 (d, J=1.9 Hz, 1H), 6.56 (dd,J=2.3 and 8.9 Hz, 1H), 6.40 (s, 1H), 6.37 (m, 1H), 6.08 (m, 1H), 3.65(br, 1H), 6.45 (br, 3H), 6.1-6.3 (m, 2H), 2.60 (m, 4H), 1.85 (m, 2H).Mass Spectrum (LCMS, ESI) calculated for C₂₈H₂₇F₃N₃O₃ 510.2 (M+H); found510.3.

EXAMPLE 383-Pyridin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) Pyridin-3-yl-propynoic acid methyl ester

The title compound was synthesized from 3-oxo-3-pyridin-3-yl-propionicacid methyl ester using the procedure described in Example 32, step (b),in 80% yield. ¹H NMR (CDCl₃) δ 8.80 (dd, J=0.7 and 2.0 Hz, 1H), 8.66(dd, J=1.7 and 4.9 Hz, 1H), 7.88 (m, 1H), 7.36 (m, 1H), 3.86 (s, 3H).

b)7-{2-[1-(2-Methoxycarbonyl-1-pyridin-3-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from pyridin-3-yl-propynoic acidmethyl ester using the procedure described in Example 17, step (a), in78% yield as an E/Z isomeric mixture. Mass Spectrum (LCMS, ESI)calculated for C₃₂H₃₅N₄O₅ 555.3 (M+H); found 455.4 (M-Boc+H).

c)7-{2-[1-(2-Methoxycarbonyl-1-pyridin-3-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized7-{2-[1-(2-methoxycarbonyl-1-pyridin-3-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 17, step(b), in 45% yield. ¹H NMR (CDCl₃) δ 8.47 (s, 1H), 8.42 (m, 1H), 7.28 (d,J=8.0 Hz, 1H), 7.22 (J=7.6 Hz, 1H), 7.02-7.13 (m, 4H), 6.86 (d, J=7.6Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 5.96 (t, J=7.6Hz, 1H), 4.28 (m, 2H), 3.67 (t, 2H), 3.54 (s, 3H), 3.24 (m, 2H), 3.12(m, 2H), 2.65 (t, J=6.5 Hz, 2H), 1.84 (m, 2H), 1.43 (s, 9H). MassSpectrum (LCMS, ESI) calculated for C₃₂H₃₇N₄O₅ 557.3 (M+H); found 457.4(M-Boc+H), 557.1.

d)3-Pyridin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester

The title compound was synthesized from7-{2-[1-(2-methoxycarbonyl-1-pyridin-3-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 26% yield. ¹H NMR (CDCl₃) δ 8.43-8.47 (br, 2H), 7.29 (d, J=8.0Hz, 1H), 7.00-7.14 (m, 5H), 6.73 (dd, J=2.4 and 8.9 Hz, 1H), 6.41 (d,J=7.1 Hz, 2H), 5.96 (t, J=7.6 Hz, 1H), 5.37 (br, 1H), 4.19 (t, J=6.7 Hz,2H), 3.54 (s, 3H), 3.33 (m, 2H), 3.24 (m, 2H), 2.97 (t, J=6.7 Hz, 2H),2.62 (t, J=6.3 Hz, 2H), 1.82 (m, 2H). Mass Spectrum (LCMS, ESI)calculated for C₂₇H₂₉N₄O₃ 457.2 (M+H); found 457.4.

e)3-Pyridin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-pyridin-3-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester using the procedure described in Example 14, step (e),in 36% yield. ¹H NMR (CDCl₃) δ 10.50 (br, 1H), 8.57 (d, 1H), 8.42 (d,1H), 7.50 (1H), 7.35 (d, 1H), 7.20 (m, 2H), 6.95 (d, 1H), 6.88 (s, 1H),6.60 (d, 1H), 6.50 (s, 1H), 6.28 (d, 1H), 6.22 (m, 1H), 5.10 (br, 1H),3.70 (m, 1H), 3.50 (m, 1H), 3.45 (m, 2H), 3.10-3.30 (m, 2H), 2.60 (m,2H), 2.50 (m, 2H), 1.85 (m, 2H). Mass Spectrum (LCMS, ESI) calculatedfor C₂₆H₂₇N₄O₃ 443.2 (M+H); found 443.3.

EXAMPLE 393-Pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) Pyridin-2-yl-propynoic acid ethyl ester

The title compound was synthesized from commercially available3-oxo-3-pyridin-2-yl-propionic acid methyl ester using the proceduredescribed in Example 32, step (b), in 76% yield. ¹H NMR (CDCl₃) δ 8.66(d, J=4.8 Hz, 1H), 7.73 (m, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.36 (m, 1H),4.31 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).

b)7-{2-[1-(2-Ethoxycarbonyl-1-pyridin-2-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from pyridin-2-yl-propynoic acidethyl ester using the procedure described in Example 17, step (a), in90% yield as an E/Z isomeric mixture. Mass Spectrum (LCMS, ESI)calculated for C₃₃H₃₇N₄O₅ 569.3 (M+H); found 469.3 (M-Boc+H).

c)7-{2-[1-(2-Methoxycarbonyl-1-pyridin-2-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-pyridin-2-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 90% yield. Transesterification occurred during the reduction,resulting in a mixture of ethyl and methyl esters. ¹H NMR (CDCl₃) δ 8.49(br, 2H), 7.30 (m, 2H), 7.15 (d, J=3.2 Hz, 1H), 7.06 (m, 1H), 6.98 (m,2H), 6.93 (m, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.47 (d, J=3.3 Hz, 1H), 5.99(t, 7.5 Hz, 1H), 4.34 (t, J=6.9 Hz, 2H), 3.73 (t, J=6.0 Hz, 2H), 3.61(s, 3H), 3.25 (m, 2H), 3.18 (m, 2H), 2.70 (m, 2H), 1.91 (m, 2H), 1.49(s, 9H). Mass Spectrum (LCMS, ESI) calculated for C₃₂H₃₆N₄O₅ 557.3(M+H); found 457.4 (M-Boc+H), 557.0.

d)3-Pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester

The title compound was synthesized from7-{2-[1-(2-methoxycarbonyl-1-pyridin-2-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 58% yield. Mass Spectrum (LCMS, ESI) calculated for C₂₇H₂₉N₄O₃457.2 (M+H); found 457.4.

e)3-Pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid methyl ester using the procedure described in Example 16, step (g),in 14% yield. ¹H NMR (CDCl₃) δ 10.29 (br, 1H), 8.41 (br, 1H), 7.35 (d,J=2.8 Hz, 1H), 6.92-7.17 (m, 3H), 6.81 (d, J=2.0 Hz, 1H), 6.55 (dd,J=2.0 and 8.8 Hz, 1H), 6.43 (d, J=2.8 Hz, 1H), 6.26 (m, 1H), 6.02 (br,1H), 3.66 (br, 1H), 3.58 (m, 1H), 3.34 (m, 2H), 3.13 (m, 2H), 2.59 (m,4H), 1.81 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C₂₆H₂₇N₄O₃443.2 (M+H); found 443.3.

EXAMPLE 403-Pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylicacid

a) Pyridin-4-yl-propynoic acid ethyl ester

The title compound was synthesized from commercially available3-oxo-3-pyridin-4-yl-propionic acid ethyl ester using the proceduredescribed in Example 32, step (b), in 65% yield. ¹H NMR (CDCl₃) δ 8.67(dd, J=1.5 and 4.5 Hz, 2H), 7.42 (dd, J=1.5 and 4.5, 2H), 4.33 (q, J=7.2Hz, 2H), 1.37 (t, J=7.2 Hz, 3H).

b)7-{2-[1-(2-Ethoxycarbonyl-1-pyridin-4-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from pyridin-4-yl-propynoic acidethyl ester using the procedure described in Example 17, step (a), in90% yield as an E/Z isomeric mixture. Mass Spectrum (LCMS, ESI)calculated for C₃₃H₃₅N₄O₅ 569.3 (M+H); found 469.4 (M-Boc+H).

c)7-{2-[1-(2-Ethoxycarbonyl-1-pyridin-4-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-pyridin-4-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 14, step(b), in 26% yield. Mass Spectrum (LCMS, ESI) calculated for C₃₃H₃₉N₄O₅571.3 (M+H); found 471.4 (M-Boc+H).

d)3-Pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylicacid ethyl ester

The title compound was synthesized from7-{2-[1-(2-ethoxycarbonyl-1-pyridin-4-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 77% yield as an E/Z isomeric mixture. Mass Spectrum (LCMS, ESI)calculated for C₂₈H₂₉N₄O₃ 469.2 (M+H); found 469.4.

e)3-Pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylicacid

The title compound was synthesized from3-pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylicacid ethyl ester using the procedure described in Example 14, step (e),in 23% yield as a single isomer. ¹H NMR (CDCl₃) δ 10.48 (br, 1H), 8.48(d, J=5.6 Hz, 2H), 7.15 (d, J=3.2, 1H), 7.08 (d, J=7.3 Hz, 1H), 7.03 (d,J=5.9, 2H), 6.88 (d, 8.9 Hz, 1H), 6.73 (m, 2H), 6.59 (d, 2.2 Hz, 1H),6.57 (d, J=2.2 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 6.25 (d, J=7.3 Hz, 1H),3.48 (br, 2H), 3.35 (br, 2H), 2.59 (m, 2H), 2.44 (br, 2H), 1.80 (m, 2H).Mass Spectrum (LCMS, ESI) calculated for C₂₆H₂₅N₄O₃ 441.19 (M+H); found441.3.

EXAMPLE 413-(2,3-Dihydro-benzofuran-5-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 3-(2,3-Dihydro-benzofuran-5-yl)-3-oxo-propionic acid ethyl ester

The title compound was synthesized from1-(2,3-dihydro-benzofuran-5-yl)-ethanone using the procedure describedin Example 32, step (a), in 47% yield. ¹H NMR (CDCl₃) 7.85 (d, 1H, J=1.4Hz), 7.78 (dd, 1H, J=1.9, 8.4 Hz), 6.81 (d, 1H, J=8.4 Hz), 4.67 (t, 2H,J=8.8 Hz), 4.21 (q, 2H, J=7.2 Hz), 3.92 (s, 2H), 3.26 (t, 2H, J=8.7Hz,), 1.26 (t, 3H, J=7.1 Hz). Mass Spectrum (LCMS, ESI) calculated forCl₃H₁₅O₄ 235.1 (M+H); found 235.2.

b) (2,3-Dihydro-benzofuran-5-yl)-propynoic acid ethyl ester

The title compound was synthesized from3-(2,3-dihydro-benzofuran-5-yl)-3-oxo-propionic acid ethyl ester usingthe procedure described in Example 32, step (b), in 65% yield. ¹H NMR(CDCl₃) * 7.42-7.38 (m, 2H), 6.77-6.74 (m, 1H), 4.62 (t, 2H, J=8.9H),4.28 (q, 2H, J=7.2 Hz), 3.21 (t, 2H, J=8.9 Hz), 1.35 (t, 3H, J=7.1 Hz).

c)7-(2-{1-[1-(2,3-Dihydro-benzofuran-5-yl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from(2,3-dihydro-benzofuran-5-yl)-propynoic acid ethyl ester and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(c1), in 52% yield as an E/Z mixture. ¹H NMR (CDCl₃) * 7.31 (d, 1H,J=7.6 Hz), 7.18-7.01 (m, 4H), 6.94 (dd, 1H, J=3.5, 7.6 Hz), 6.82-6.71(m, 3H), 6.56-6.48 (m, 1H), 6.10 (s, 0.6H), 6.00 (s, 0.4H), 4.62 (q, 2H,J=8.8 Hz), 4.39-4.35 (m, 2H), 4.13 (q, 0.8H, J=7.1 Hz), 3.98 (q, 1.2H.J=7.1 Hz), 3.76 (t, 2H, J=5.9 Hz), 3.23-3.14 (m, 4H), 2.73 (t, 2H,J=6.64 Hz), 1.95-1.89 (m, 2H), 1.52 (s, 9H), 1.21 (t, 1.2H, J=7.1 Hz),1.00 (t, 1.8 Hz, J=7.1 Hz).

The titled compound is prepared using the procedures described inExample 18, step (e), followed by Example 16, step (e), and Example 18,step (g).

EXAMPLE 423-benzo[1,3]dioxol-5-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 5-(2,2-Dibromo-vinyl)-benzo[1,3]dioxole

To a solution of piperonal (4.5 g, 30 mmol) and triphenylphosphine (24g, 90 mmol) in DCM (120 mL) in an ice-water bath was added a solution ofcarbontetrabromide (15 g, 45 mmol) over a 10 minutes period. After theaddition completed, the ice-water bath was removed, the reaction stirredat ambient temperature for 2 h, and then quenched with saturated NaHCO₃.Aqueous was separated, and extracted with dichloromethane (2 times). Theorganic layers were combined, dried over Na₂SO₄, filtered, andconcentrated to give a redish colored residue, that was filtered througha short path silica gel plug, eluting with DCM/hexane (10% to 20%).Concentration of the filtrate gave the title compound (6.5 g, 74% yield)as a pale yellow liquid. ¹H NMR (CDCl₃) * 7.36 (s, 1H), 7.18 (d, 1H,J=1.6 Hz), 6.95 (dd, 1H, J=1.5, 8.1 Hz), 6.79 (d, 1H, J=8.1 Hz), 5.99(s, 2H).

b) 5-Ethynyl-benzo[1,3]dioxole

To a solution of 5-(2,2-dibromo-vinyl)-benzo[1,3]dioxole (1.47 g, 5.0mmol) in THF (10 mL) at −78° C. was added 2.0 M solution ofn-butyllithium (5.5 mL, in cyclohexane) over 5 minutes period. After theaddition completed, the reaction was stirred for 1 h, and then quenchedwith saturated NH₄Cl. The mixture was allowed to warm up to roomtemperature. THF was removed. The aqueous was extracted with ethylacetate. The organic layer washed with water, brine, dried over Na₂SO₄,concentrated, and flash chromatographed on silica gel, eluting withDCM/hexane (5 to 10%) to give the title compound (0.64 g, 95% yield) asan orange oil. ¹H NMR (CDCl₃) *7.02 (dd, 1H, J=1.6, 8.1 Hz), 6.93 (d,1H, J=1.6 Hz), 6.75 (d, 1H, J=8.0 Hz), 5.98 (s, 2H), 2.97 (s, 1H).

c) Benzo[1,3]dioxol-5-yl-propynoic acid ethyl ester

The title compound was synthesized from 5-ethynyl-benzo[1,3]dioxole and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 23, step(c), in 54% yield. ¹H NMR (CDCl₃) *7.16 (dd, 1H, J=1.6, 8.1 Hz), 7.00(d, 1H, J=1.6 Hz,), 6.80 (d, 1H, J=8.1 Hz,), 6.02 (s, 2H), 4.29 (q, 2H,J=7.2 Hz,), 1.35 (t, 3H, J=7.2 Hz).

d)7-{2-[1-(1-Benzo[1,3]dioxol-5-yl-2-ethoxycarbonyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from benzo[1,3]dioxol-5-yl-propynoicacid ethyl ester and7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(c1), in 39% yield as an E/Z mixture. ¹H NMR (CDCl₃) *7.32 (d, 1H, J=7.6Hz), 7.10-7.04 (m, 2H), 7.00-6.90 (m, 2H), 6.85-6.71 (m, 4H), 6.56-6.49(m, 1H), 6.10 (s, 0.6H), 6.04 (s, 0.4H), 6.03 (s, 0.8H), 6.00 (s, 1.2H),4.40-4.35 (m, 2H), 4.13 (q, 0.8H, J=7.1 Hz), 3.98 (q, 1.2H, J=7.1 Hz),3.76 (t, 2H, J=5.9 Hz), 3.20 (t, 2H, 6.8 Hz), 2.73 (t, 2H, 6.7 Hz),1.95-1.89 (m, 2H), 1.519 (s, 5.4H), 1.516 (s, 3.6H), 1.22 (t, 1.2H,J=7.1 Hz), 1.01 (t, 1.8H, J=7.1 Hz). Mass Spectrum (LCMS, ESI)calculated for C₃₀H₂₉N₃O₅ 512.3 (M-Boc+1); found 512.3.

e)7-{2-[1-(1-Benzo[1,3]dioxol-5-yl-2-ethoxycarbonyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-{2-[1-(1-Benzo[1,3]dioxol-5-yl-2-ethoxycarbonyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 89% yield as a yellow oil. ¹H NMR (CDCl₃) *7.30 (d, 1H, J=7.6Hz), 7.21-7.16 (m, 2H), 7.08 (d, 1H, J=2.4 Hz), 6.94 (d, 1H, J=7.6 Hz),6.82 (dd, 1H, J=2.4, 8.9 Hz), 6.73-6.68 (m, 2H), 6.62 (d, 1H, J=0.7 Hz),6.42 (d, 1H, J=3.2 Hz), 5.90-5.89 (m, 2H), 4.36 (t, 2H, J=6.9 Hz), 4.04(q, 2H, J=7.1 Hz), 3.75 (t, 2H, J=6.0 Hz), 3.24-3.15 (m, 4H), 2.72 (t,2H, J=6.6 Hz), 1.95-1.89 (m, 2H), 1.51 (s, 9H), 1.10 (t, 2H, J=7.1 Hz).

f)3-Benzo[1,3]dioxol-5-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-{2-[1-(1-benzo[1,3]dioxol-5-yl-2-ethoxycarbonyl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(e), in 53% yield as a yellow oil. ¹H NMR (CDCl₃) *7.20-7.15 (m, 2H),7.09-7.07 (m, 2H), 6.82 (dd, 1H, J=2.4, 9.1 Hz), 6.73-6.68 (m, 2H), 6.62(bs, 1H), 6.47 (d, 1H, J=7.2 Hz), 6.42 (d, 1H, J=3.0 Hz), 5.92-5.88 (m,3H), 4.92 (bs, 1H), 4.28 (t, 2H, J=7.0 Hz), 4.04 (q, 2H, J=7.1 Hz),3.41-3.38 (m, 2H), 3.28-3.15 (m, 2H), 3.03 (t, 2H, J=7.0 Hz), 2.69 (t,2H, J=6.3 Hz), 1.93-1.87 (m, 2H), 1.10 (t, 3H, J=7.1 Hz).

g)3-Benzo[1,3]dioxol-5-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-benzo[1,3]dioxol-5-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 87% yield as a yellow oil. ¹H NMR (CDCl₃) *10.46 (bs, 1H), 7.45 (d,1H, J=3.2 Hz), 7.26-7.24 (m, 1H), 7.08 (d, 1H, J=7.3 Hz), 6.83 (d, 1H,J=2.3 Hz), 6.69-6.60 (m, 4H), 6.45 (d, 1H, 3.1 Hz), 6.26 (d, 1H, 7.3Hz), 6.03 (dd, 1H, J=4.6, 11.1 Hz), 5.88-5.86 (m, 2H), 3.65-3.60 (m,1H), 3.74-3.42 (m, 1H), 3.38-3.35 (m, 2H), 3.28-3.10 (m, 2H), 2.59-2.43(m, 4H), 1.84-1.80 (m, 2H). Mass Spectrum (LCMS, ESI) calculated forC₂₈H₂₈N₃O₅ 486.2 (M+H); found 486.3.

EXAMPLE 433-(5-Methanesulfonyl-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethyoxy]-indol-1-yl}-propionicacid

a) Trimethyl-triethoxyprop-1-ynyl-silane

Boron trifluoride diethyl etherate (36.0 mL, 280 mmol) was added todiethyl ether (50 mL) under argon. The mixture was transferred to adropping funnel and added dropwise under argon to a solution oftetraethyl orthocarbonate (40.0 g, 208 mmol) in diethyl ether (100 mL)at 0° C. After the addition was complete, the mixture was stirred for 5min and then cooled to −78° C. In a separate reaction flask,n-butyllithium (166 mL, 2.5 M solution in hexanes, 416 mmol) was addeddropwise to a solution of trimethylsilyl acetylene (59.0 mL, 416 mmol)in diethyl ether (200 mL) at 0° C. under argon. After stirring for 1 hat 0° C., the solution was cooled to −78° C. This solution was added viacannula to the triethoxycarbenium tetrafluoroborate formed previously.The mixture was stirred at −78° C. for 1 h before being warming to roomtemperature. Saturated aqueous potassium carbonate was added and mixturewas extracted with diethyl ether. The organic extracts were dried withmagnesium sulfate and the solvent was removed under reduced pressure togive the title compound (50.0 g, 100% yield) as yellow oil. ¹H NMR(CDCl₃) * 3.68(q, 6H, J=7.2 Hz), 1.23 (t, 9H, J=7.2 Hz), 0.20, (s, 9H).

b) 3,3,3-Triethoxypropyne

A solution of sodium hydroxide (0.14 g, 3.60 mmol) in water (50 mL) wasadded to a solution of trimethyl-triethoxyprop-1-ynyl-silane (50.0 g,208 mmol) in ethanol (250 mL). After stirring for 1 hour at roomtemperature, water was added and the mixture was extracted with ethylacetate. The organic extracts were dried with magnesium sulfate and thesolvent was removed under reduced pressure to give the title compound(20.0 g, 52% yield) as yellow oil. ¹H NMR (CDCl₃) * 3.70 (q, 6H, J=8.0Hz), 2.56 (s, 1H) 1.24 (t, 9H, J=8.0 Hz).

c) 3-Bromo-5-methylsulfanyl-pyridine

Sodium thiomethoxide (1.6 g, 23 mmol) was added to a solution of3,5-dibromopyridine (5 g, 21 mmol) in DMF (25 mL). After stirringovernight at room temperature, the reaction mixture was diluted withethyl acetate and washed several times with brine. The extracts weredried over magnesium sulfate and the solvent was removed under reducedpressure. The crude material was chromatographed on silica (10% ethylacetate/hexanes) to give the title compound (3.8 g, 89% yield) as aclear oil.

d) 3-Bromo-5-methanesulfonyl-pyridine

MCPBA (9.2 g, 38 mmol) was added slowly to a solution of3-bromo-5-methylsulfanyl-pyridine (3.8 g, 19 mmol) in dichloromethane(50 mL). After stirring for 30 minutes, the reaction was diluted withdichloromethane and quenched carefully with 1N NaOH. The product wasextracted with dichloromethane and dried over magnesium sulfate. Thesolvent was removed under reduced pressure to give title compound (2.7g, 82% yield) as a white solid.

e) 3-Methanesulfonyl-5-triethoxyprop-1-ynyl-pyridine

A solution of 3-bromo-5-methanesulfonyl-pyridine (1.00 g, 4.20 mmol),3,3,3-triethoxypropyne (1.75 g, 9.4 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.21 mmol),copper(I) iodide (0.08 g, 0.42 mmol), triethylamine (1.80 mL, 12.7 mmol)and dichloromethane (40 mL) was heated at reflux for 48 h. The mixturewas cooled to room temperature and the solvent was removed under reducedpressure. The crude product was chromatographed on silica (30% ethylacetate/hexanes) to give the title compound (1.2 g, 87% yield) as yellowsolid. ¹H NMR (CDCl₃) * 9.08(d, 1H, J=2.4 Hz), 8.91 (d, 1H J=2.0), 8.28(t, 1H, J=2.0 Hz), 3.75 (q, 6H, J=7.2), 3.13 (s, 3H), 1.29 (t, 9H,J=7.2).

f) (5-Methanesulfonyl-pyridin-3-yl)-propynoic acid ethyl ester

p-Toluenesulfonic acid monohydrate (1.39 g, 0.73 mmol) was added to asolution of 3-methanesulfonyl-5-triethoxyprop-1-ynyl-pyridine (1.20 g,3.70 mmol) in toluene (40 mL). After stirring overnight at roomtemperature, the solvent was removed under reduced pressure. The crudeproduct was chromatographed on silica (30% ethyl acetate/hexanes) togive the title compound (0.55 g, 53% yield) as a white solid. ¹H NMR(CDCl₃) * 9.17 (d, 1H, J=2.4 Hz), 9.03 (d, 1H J=2.0), 8.40 (t, 1H, J=2.0Hz), 4.35 (q, 6H, J=8.0), 3.14 (s, 3H), 1.38 (t, 9H, J=8.0).

g)7-(2-{1-[2-Ethoxycarbonyl-1-(5-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from(5-methanesulfonyl-pyridin-3-yl)-propynoic acid ethyl ester and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(d1), in 80% yield. Mass Spectrum (LCMS, ESI) calculated forC₂₉H₃₁N₄O₅S: 547.2 (M-Boc+H); found 547.3 (-Boc).

h)7-(2-{1-[2-Ethoxycarbonyl-1-(5-methanesulfonyl-pyridin-3-yl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihyrdro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(5-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 25% yield. ¹H NMR (CDCl₃) * 9.03 (d, 1H, J=2.0 Hz), 8.71 (d, 1H,J=2.0 Hz), 7.97 (t, 1H, J=2.0 Hz), 7.30 (m, 2H), 7.20 (d, 1H, J=3.6 Hz),6.84 (dd, 1H, J=1.6, 6.8 Hz), 6.93 (m, 2H), 6.52 (d, 1H, J=3.2 Hz), 6.12(t, 1H, J=3.2 Hz).

i)3-(5-Methanesulfonyl-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}propionicacid ethyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(5-methanesulfonyl-pyridin-3-yl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihyrdro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 32% yield. ¹H NMR (CD₃OD) * 8.96 (s, 1H), 8.67 (s, 1H), 8.16 (s,1H), 7.96 (s, 1H), 7.49 (d, 1H, J=2.8 Hz), 7.43 (d, 1H, J=7.2 Hz), 7.29(d, 1H, J=8.8), 7.06 (d, 1H, J=2.0 Hz), 6.76 (dd, 1H, J=2.4, 6.4 Hz),6.63 (d, 1H, J=7.6 Hz), 6.48 (d, 1H, J=2.8 Hz), 6.40 (t, 1H, J=3.2 Hz),4.24 (t, 2H, J=6.0 Hz), 4.01 (m, 2H), 3.51 (m, 2H), 3.42 (t, 2H, J=5.6Hz), 3.06 (t, 2H, J=6.0 Hz), 2.97 (s, 3H), 2.74 (t, 2H, J=6.0 Hz), 1.99(m, 2H), 1.05 (t, 3H, J=6.8 Hz).

j)Methanesulfonyl-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound was synthesized from3-(5-Methanesulfonyl-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}propionicacid ethyl ester using the procedure described in Example 18, step (g),in 30% yield. ¹H NMR (CDCl₃) *10.50 (s, 1H), 8.91 (s, 1H), 8.61 (s, 1H),7.89 (s, 1H), 7.37 (d, 1H, J=2.8 Hz), 7.10 (d, 1H, J=7.6 Hz), 7.01 (d,1H, J=8.8 Hz), 6.83 (d, 1H, J=1.6 Hz), 6.55 (d, 1H, J=8.8 Hz), 6.43 (d,1H, J=2.8 Hz), 6.25 (d, 1H, J=7.6 Hz), 6.14 (t, 1H, J=7.2 Hz), 3.74 (m,2H), 3.34 (m, 2H), 3.23 (m, 2H), 3.10 (m, 2H), 2.93 (s, 3H), 2.59 (t,2H, J=6.0 Hz), 1.78 (m, 2H). Mass Spectrum (LCMS, ESI) calculated forC₂₇H₂₉N₄O₃S: 521.2 (M+H); found 521.3.

EXAMPLE 443-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-phenyl-propionicacid

a) [6-(2-Hydroxy-ethyl)-pyridin-2-yl]-methyl-carbamic acid tert-butylester

The title compound was synthesized from[6-(tert-butoxycarbonyl-methyl-amino)-pyridin-2-yl]-acetic acid ethylester (synthetic methodology described in WO 98/14192) using theprocedure described in Example 16, step (a), in 80% yield. ¹H NMR(Cl₃CD), δ: 7.55 (m, 2H), 6.85 (dd, 1H, J=1.1, 6.7 Hz), 4.00 (m, 2H),3.37 (s, 3H), 2.97 (m, 2H), 1.53 (s, 9H).

b) Methyl-{6-[2-(3-methyl-4-nitro-phenoxy)-ethyl]-pyridin-2-yl}-carbamicacid tert-butyl ester

The title compound was synthesized from[6-(2-hydroxy-ethyl)-pyridin-2-yl]-methyl-carbamic acid tert-butyl esterand the commercially available 3-methyl-4-nitro-phenol using theprocedure described in Example 16, step (b), in 81% yield. ¹H NMR(Cl₃CD), δ: 1.52 (s, 9H), 2.62 (s, 3H), 3.21 (t, 2H, J=8.00 Hz), 3.36(s, 3H), 4.44 (t, 2H, J=8.00 Hz), 6.80 (m, 2H), 6.94 (dd, 1H, J=2.4, 5.6Hz), 7.55 (m, 2H), 8.05 (d, 1H, J=8.8 Hz).

c) {6-[2-(1H-Indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acidtert-butyl ester

The title compound was synthesized frommethyl-{6-[2-(3-methyl-4-nitro-phenoxy)-ethyl]-pyridin-2-yl}-carbamicacid tert-butyl ester using the procedure described in Example 16, step(c), in 48% yield. H¹ NMR (Cl₃CD), δ: 8.09 (1H, br s), 7.55 (m, 1H),7.49 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=8.7 Hz), 7.17 (m, 1H), 7.14 (d,1H, J=2.4 Hz), 6.98 (d, 1H, J=7.3 Hz), 6.85 (dd, 1H, J=2.4, 6.8 Hz),6.80 (m, 2H), 6.46 (m, 1H), 4.39 (t, 2H, J=6.8 Hz), 3.39 (s, 3H), 3.22(t, 2H, J=6.8 Hz), 1.51 (s, 9H).

d)3-(5-{2-[6-(tert-Butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-phenyl-acrylicacid ethyl ester

The title compound was synthesized from{6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acidtert-butyl ester and the commercially available phenyl propynoic acidethyl ester using the procedure described in Example 16, step (dl), in81% yield as an E/Z isomeric mixture. H¹ NMR (Cl₃CD), δ: 7.57-7.53 (m,1H), 7.52-7.46 (m, 1.5H), 7.44 (m, 1H), 7.41-7.34 (m, 2.5H), 7.29 (m,1H), 7.12 (d, 0.5H, J=2.1 Hz), 7.07 (m, 1.5H), 6.97 (m, 1.5H), 6.76 (m,1H), 6.70 (m, 0.5H), 6.59 (d, 0.5H, J=3.2 Hz), 6.51 (d, 0.5H, J=3.5 Hz),6.22 (s, 0.5H), 6.15 (s, 0.5H), 4.38 (m, 2H), 4.09 (c, 1.5H, J=7.0 Hz),4.01 (c, 1.5H, J=7.2 Hz), 3.39 (m, 3H), 3.21 (m, 2H), 1.52 (s, 9H), 1.16(t, 1.5H, J=7.2 Hz), 1.03 (t, 1.5H, J=7.0 Hz).

e)3-(5-{2-[6-(tert-Butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-phenyl-propionicacid ethyl ester

The title compound was synthesized from3-(5-{2-[6-(tert-butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-phenyl-acrylicacid ethyl ester using the procedure described in Example 16, step (e),in 97% yield. H¹ NMR (Cl₃CD), δ: 7.54 (m, 1H) 7.48 (d, 1H, J=7.2 Hz),7.29-7.16 (m, 7H), 7.10 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=0.8, 7.2 Hz),6.80 (dd, 1H, J=2.4, 9.2 Hz), 6.45 (dd, 1H, J=0.8, 3.6 Hz), 6.02 (t, 1H,J=7.6 Hz), 4.37 (t, 2H, J=8.0 Hz), 4.04 (c, 2H, J=8.0 Hz), 3.38 (s, 3H),3.27 (m, 2H), 3.20 (t, 2H, J=8.0 Hz), 1.51 (s, 9H), 1.10 (t, 3H, J=8.0Hz).

f)3-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-phenyl-propionicacid ethyl ester

The title compound was synthesized from3-(5-{2-[6-(tert-butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-phenyl-propionicacid ethyl ester using the procedure described in Example 16, step (f),in 73% yield. H¹ NMR (Cl₃CD), δ: 7.40 (m, 1H) 7.30-7.25 (m, 3H),7.20-7.16 (m, 4H), 7.10 (d, 1H, J=2.4 Hz), 6.81 (dd, 1H, J=2.4, 8.9 Hz),6.56 (d, 1H, J=7.2 Hz), 6.44 (d, 1H, J=3.2 Hz), 6.24 (d, 1H, J=8.2 Hz),6.01 (t, 1H, J=7.6 Hz), 4.55 (br s, 1H), 4.32 (t, 2H, J=8.0 Hz), 4.03(c, 2H, J=8.0 Hz), 3.26 (m, 1H), 3.09 (t, 3H, J=8.0 Hz), 2.89 (s, 3H),1.08 (t, 3H, J=8.0 Hz).

g)3-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-phenyl-propionicacid

The title compound was synthesized from3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-phenyl-propionicacid ethyl ester using the procedure described in Example 16, step (g),in 66% yield. H¹ NMR (DMSO-d6), δ: 7.66 (m, 1H). 7.39-7.19 (m, 7H), 7.04(d, 1H, J=2.4 Hz), 6.70 (dd, 1H, J=2.4, 9.2 Hz), 6.43 (d, 1H, J=6.8 Hz),6.35 (m, 2H), 6.25 (d, 1H, J=8.0 Hz), 5.94 (m, 1H), 4.25 (t, 2H, J=8.0Hz), 3.39 (m, 1H), 2.94 (t, 3H, J=8.0 Hz), 2.74 (m, 3H). Mass Spectrum(LCMS, ESI) calculated for C₂₅H₂₆N₃O₃ 416.2, (M+1); found: 416.3.

EXAMPLE 453-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-quinolin-3-yl-propionicacid

a) 3-Ethynyl-quinoline

The title compound was synthesized from the commercially available3-bromo quinoline using the procedures described in Example 18, step (a)and step (b), in 68% yield. H¹ NMR (Cl₃CD), δ: 8.95 (d, 1H, J=2.0 Hz),8.29 (d, 1H, J=2.0 Hz), 8.09 (d, 1H, J=8.8 Hz), 7.80 (m, 1H), 7.74 (m,1H), 7.60 (m, 1H), 3.28 (s, 1H).

b) Quinolin-3-yl-propynoic acid ethyl ester

The title compound was synthesized from 3-ethynyl-quinoline using theprocedure described in Example 23, step (c), in 34% yield. H¹ NMR(Cl₃CD), δ: 8.99 (d, 1H, J=2.0 Hz), 8.40 (d, 1H, J=2.0 Hz), 8.11 (d, 1H,J=8.4 Hz), 7.80 (m, 2H), 7.60 (m, 1H), 4.34 (q, 2H, J=7.2 Hz), 1.38 (t,3H, J=7.2 Hz).

c)3-(5-{2-[6-(tert-Butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-quinolin-3-yl-acrylicacid ethyl ester

The title compound was synthesized from{6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acidtert-butyl ester and quinolin-3-yl-propynoic acid ethyl ester, using theprocedure described in Example 16, step (d1), in 48% yield, as an E/Zisomeric mixture. H¹ NMR (Cl₃CD), δ: 8.91 (d, 0.3H, J=2.1 Hz), 8.88 (d,0.3H, J=2.3 Hz), 8.17 (d, 0.7H, J=8.8 Hz), 8.14-8.11 (m, 1H), 7.97 (d,0.3H, J=2.0 Hz), 7.82-7.74 (m, 2H), 7.60 (m, 1H), 7.53 (m, 1H), 7.49 (m,1H), 7.17 (m, 1H), 7.11 (m, 1H), 6.92-6.97 (m, 2H), 6.78 (dd, 0.7H,J=2.5, 9.0 Hz), 6.70 (dd, 0.3H, J=2.5, 9.0 Hz), 6.64 (d, 0.3H, J=3.2Hz), 6.55 (d, 0.7H, J=3.5 Hz), 6.39 (s, 0.3H), 6.32 (s, 0.7H), 4.39 (m,2H), 4.10 (q, 1.4H, J=7.2 Hz), 4.04 (q, 0.6H, J=7.2 Hz), 1.39 (s, 0.9H),1.38 (s, 2.1H), 3.21 (m, 2H), 1.51 (s, 9H), 1.14 (t, 2.1H, J=7.2 Hz),1.05 (t, 0.9H, J=7.2 Hz).

d)3-(5-{2-[6-(tert-Butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-quinolin-3-yl-propionicacid ethyl ester

The title compound was synthesized from3-(5-{2-[6-(tert-butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-quinolin-3-yl-acrylicacid ethyl ester using the procedure described in Example 18, step (d),in 53% yield. H¹ NMR (Cl₃CD), δ: 8.88 (m, 1H), 8.06 (d, 1H, J=8.6 Hz),7.87 (m, 1H), 7.72 (m, 1H), 7.68 (m, 2H), 7.55-7.47 (m, 3H), 7.24 (m,2H), 7.11 (d, 1H, J=2.3 Hz), 6.95 (d, 1H, J=7.2 Hz), 6.81 (dd, 1H,J=2.3, 8.8 Hz), 6.51 (d, 1H, J=3.2 Hz), 6.23 (t, 1H, J=7.4 Hz), 4.36 (t,2H, J=6.7 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.38 (m, 5H), 3.19 (t, 2H, J=6.7Hz), 1.51 (s, 9H), 1.11 (t, 3H, J=7.2 Hz).

e)3-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-quinolin-3-yl-propionicacid ethyl ester

The title compound was synthesized from3-(5-{2-[6-(tert-butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-quinolin-3-yl-propionicacid ethyl ester using the procedure described in Example 16, step (f),in 20% yield. H¹ NMR (Cl₃CD), δ: 8.83 (d, 1H, J=2.3 Hz), 8.08 (d, 1H,J=8.4 Hz), 7.89 (m, 1H), 7.75 (m, 1H), 7.71 (m, 1H), 7.55 (m, 1H), 7.40(m, 1H), 7.24 (d, 1H, J=3.2 Hz), 7.23 (m, 1H), 7.14 (d, 1H, J=2.3 Hz),6.84 (dd, 1H, J=2.5, 9.0 Hz), 6.57 (d, 1H, J=7.2 Hz), 6.52 (d, 1H, J=3.2Hz), 6.25 (m, 2H), 4.52 (br s, 1H), 4.35 (t, 2H, J=6.9 Hz), 4.10 (q, 2H,J=7.2 Hz), 3.43 (m, 2H), 3.10 (t, 2H, J=6.9 Hz), 2.91 (m, 3H), 1.14 (t,3H, J=7.2 Hz).

f)3-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-quinolin-3-yl-propionicacid

The title compound was synthesized from3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-quinolin-3-yl-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 60% yield. H¹ NMR (DMSO-d6) δ: 8.91 (d, 1H, J=2.3 Hz), 8.33 (d, 1H,J=2.0 Hz), 7.96 (d, 1H, J=8.6 Hz), 7.90 (m, 1H), 7.77 (d, 1H, J=3.2 Hz),7.59 (m, 1H), 7.72 (m, 1H), 7.52 (d, 1H, J=9.0 Hz), 7.28 (m, 1H), 7.06(d, 1H, J=2.5 Hz), 6.71 (dd, 1H, J=2.3, 8.8 Hz), 6.43 (m, 2H), 6.33(m,1H), 6.25 (d, 1H, J=8.6 Hz), 6.21 (m, 1H), 4.25 (t, 2H, J=6.7 Hz), 3.56(m, 2H), 2.93 (t, 2H, J=6.7 Hz), 2.73 (m, 3H). Mass Spectrum (LCMS, ESI)calculated for C₂₈H₂₇N₄O₃ 467.2, (M+1); found: 467.2.

EXAMPLE 463-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-pyridin-3-yl-propionicacid

a)3-(5-{2-[6-(tert-Butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-pyridin-3-yl-acrylicacid methyl ester

The title compound was synthesized from{6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acidtert-butyl ester and pyridin-3-yl-propynoic acid methyl ester, using theprocedure described in Example 16, step (d1), in a 96% yield, as an E/Zisomeric mixture. ¹H NMR (Cl₃CD), δ: 8.74-8.64 (m, 2H), 7.68 (m, 0.4),7.57-7.48 (m, 2H), 7.45 (m, 0.6H), 7.38 (m, 0.4H), 7.28 (m, 0.6H), 7.13(m, 1H), 7.08 (m, 1H), 6.96 (d, 1H, J=7.0 Hz), 6.88 (d, 0.4H, J=3.5 Hz),6.80-6.66 (m, 1.6H), 6.61 (d, 0.6H, J=3.2 Hz), 6.54 (d, 0.4H, J=3.5 Hz),6.26 (s, 0.4H), 6.24 (s, 0.6H), 4.39 (m, 2H), 3.67 (s, 1.2H), 3.61 (s,1.8H), 3.39 (m, 3H), 3.20 (m, 2H), 1.51 (s, 9H).

b)3-(5-{2-[6-(tert-Butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-pyridin-3-yl-propionicacid methyl ester

The title compound was synthesized from3-(5-{2-[6-(tert-butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-pyridin-3-yl-acrylicacid methyl ester using the procedure described in Example 16, step (e),in 53% yield. ¹H NMR (Cl₃CD), δ: 8.55 (d, 1H, J=2.3 Hz), 8.51 (dd, 1H,J=1.6, 8.5 Hz), 7.52 (m, 2H), 7.21-7.15 (m, 3H), 7.37 (m, 1H), 7.10 (d,1H, J=2.3 Hz), 6.96 (dd, 1H, J=0.6, 7.1 Hz), 6.81 (dd, 1H, J=2.4, 8.9Hz), 6.48 (d, 1H, J=3.1 Hz), 6.04 (t, 1H, J=7.6 Hz), 4.36 (t, 2H, J=8.0Hz), 3.62 (s, 3H), 3.38 (s, 3H), 3.31 (m, 2H), 3.19 (t, 2H, J=8.0 Hz),1.51 (s, 9H).

c)3-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-pyridin-3-yl-propionicacid methyl ester

The title compound was synthesized from3-(5-{2-[6-(tert-butoxycarbonyl-methyl-amino)-pyridin-2-yl]-ethoxy}-indol-1-yl)-3-pyridin-3-yl-propionicacid methyl ester using the procedure described in Example 16, step (f),in 55% yield. ¹H NMR (Cl₃CD), δ: 8.55 (d, 1H, J=2.3 Hz), 8.51 (dd, 1H,J=1.5, 4.8 Hz), 7.37 (m, 2H), 7.18 (m, 3H), 7.10 (d, 1H, J=2.4 Hz), 6.82(dd, 1H, J=2.4, 8.9 Hz), 6.55 (d, 1H, J=7.2 Hz), 6.47 (d, 1H, J=2.9 Hz),6.23 (d, 1H, J=8.2 Hz), 6.04 (t, 1H, J=7.5 Hz), 4.54 (br s, 1H), 4.33(t, 2H, J=8.0 Hz), 3.62 (s, 3H), 3.31 (m, 2H), 3.09 (t, 2H, J=8.0 Hz),2.89 (m, 3H).

d)3-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-pyridin-3-yl-propionicacid

The title compound was synthesized from3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-pyridin-3-yl-propionicacid methyl ester using the procedure described in Example 16, step (g),in 42% yield. ¹H NMR (DMSO-d6) δ: 8.62 (br s, 1H), 8.44 (br s, 1H), 7.71(m, 2H), 7.46 (d, 1H, J=8.9 Hz), 7.29 (m, 2H), 7.05 (d, 1H, J=2.3 Hz),6.71 (dd, 1H, J=2.3, 8.9 Hz), 6.43 (d, 1H, J=7.1 Hz), 6.39 (d, 1H, J=3.1Hz) 6.35 (m, 1H), 6.25 (d, 1H, J=8.2 Hz), 4.25 (t, 2H, J=8.0 Hz), 6.02(m, 1H), 3.49 (m, 2H), 2.93 (t, 2H, J=8.0 Hz), 2.74 (m, 3H). MassSpectrum (LCMS, ESI) calculated for C₂₅H₂₅N₄O₃ 417.2, (M+1); found:417.3.

EXAMPLE 473-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoic acid

a) 3-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoicacid ethyl ester

The title compound was synthesized from2-(6-methylamino-pyridin-2-yl)-ethanol and3-(5-hydroxy-indol-1-yl)-hexanoic acid ethyl ester using the proceduredescribed in Example 14, step (c), in 25% yield. The crude product wasused in the next step without further purification.

b) 3-{5-[2-(6-Methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoicacid

The title compound was synthesized from3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoic acidethyl ester using the procedure described in Example 14, step (e), in51% yield. ¹H NMR (CDCl₃) δ 7.50 (dd, 1H, J=7.4, 8.8 Hz), 7.38 (d, 1H,J=9.0 Hz), 7.21 (d, 1H, J=3.2 Hz), 6.91 (d, 1H, J=2.4 Hz), 6.69 (dd, 1H,J=2.4, 8.9 Hz), 6.49 (d, 1H, J=7.3 Hz), 6.43 (d, 1H, J=3.1 Hz), 6.33 (d,1H, J=8.7 Hz), 4.92-2.84 (m, 1H), 3.93-3.88 (m, 1H), 3.79-3.75 (m, 1H),2.92-2.66 (m, 7H), 1.87-1.77 (m, 2H), 1.26-1.14 (m, 1H), 1.13-1.01 (m,1H), 0.84 (t, 3H, J=7.2 Hz). Mass spectrum (LCMS, ESI) calculated forC₂₂H₂₈N₃O₃ 382.2 (M+H); found 382.3.

EXAMPLE 483-{5-[2-(2-Methyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-ethyl]-indol-1-yl}-propionicacid

a) 4-(1H-Indol-5-yl)-butyronitrile

A mixture of 5-bromoindole (0.25 g, 1.25 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.12 mmol) was stirredunder a nitrogen atmosphere for 10 minutes. 3-cyanopropyl zinc bromide[0.5 M in THF] (5.0 mL, 2.50 mmol) was added to the mixture and heatedin the microwave at 100° C. for 15 minutes. The solvent was removed andthe crude mixture was purified via column chromatography with silicagel, eluting with hexane/ethyl acetate (4/1) to afford the titlecompound in 63% yield. ¹H NMR (CDCl₃) δ 8.22 (br, 1H), 7.43 (s, 1H),7.31 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.49 (s,1H), 2.86 (t, J=7.3 Hz, 2H), 2.28 (t, J=7.2 Hz, 2H), 2.02 (m, 2H). MassSpectrum (LCMS, ESI) calculated for C₁₂H₁₃N₂ 185.1 (M+H); found 185.1.

b) 5-Bromo-1-triisopropylsilanyl-1H-indole

Lithium hexamethyldisilazane [1.0 M] (44.7 mL, 44.4 mmol) was added to asolution of 5-bromo-1H-indole (7.30 g, 37.0 mmol) in tetrahydrofuran (50mL) at room temperature. After stirring for 5 minutes, triisopropylsilylchloride (8.62 g, 44.4 mmol) was added to reaction mixture and stirredfor 30 minutes. Water was added to quench the reaction and the solventwas removed under reduced pressure to give the crude mixture, which waspurified via column chromatography on silica gel (9:1 hexane/ethylacetate) to give the title compound in 92% yield. ¹H NMR (CDCl₃) δ 7.74(d, J=1.8, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.22 (m, 2H), 6.55 (d, J=3.1 Hz,1H), 1.65 (m, 3H), 1.12 (d, J=7.5 Hz, 18H).

c) 4-(1-Triisopropylsilanyl-1H-indol-5-yl)-butyronitrile

Method c1

A mixture of 5-bromo-1-triisopropylsilanyl-1H-indole (4.30 g, 12.2mmol), tetrakis(triphenylphosphine)-palladium (0) (1.41 g, 1.22 mmol),and 3-cyanopropyl zinc bromide [0.5 M in THF] (50 mL, 24.4 mmol) washeated at 70° C. overnight. The reaction was cooled and 1.0 N HCl (50mL) was added. The crude product was extracted with methylene chloride(3×30 mL), and the combined organic layers were washed with water,brine, and then dried over Na₂SO₄. Removal of solvent gave a crudemixture which was purified via column chromatography, eluting withhexane/ethyl acetate (9/1) to give the title compound (64% yield).

Method c2

Lithium hexamethyldisilazane [1.0 M] (0.90 mL, 0.90 mmol) was addeddropwise to a solution of 4-(1H-indol-5-yl)-butyronitrile (0.15 g, 0.82mmol) in THF (2 mL) at −78° C. under nitrogen. After 5 minutes,triisopropylsilyl chloride (0.40 mL, 0.90 mmol) was added and thereaction was warmed to room temperature and stirred for an additional 4h. Water was added to quench the reaction and the solvent was removedunder reduced pressure. The crude mixture was purified via columnchromatography with silica gel, eluting with hexane/ethyl acetate (4/1)to give the title compound (95% yield). ¹H NMR (CDCl₃) δ 7.45 (d, 2H),7.25 (m, 1H), 6.90 (m, 1H), 6.55 (m, 1H), 2.86 (t, 2H), 2.30 (t, 2H),2.06 (m, 2H), 1.67 (m, 3H), 1.10 (d, 18H).

d) 5-(1-Triisopropylsilanyl-1H-indol-5-yl)-pentan-2-one

Methyl magnesium iodide [3 M in ether] (12.0 mL, 36.0 mmol) was added toa solution of 4-(1H-indol-5-yl)-butyronitrile (6.14 g, 18.0 mmol) inether (50 mL) at 78° C. After addition, the reaction mixture was warmedto room temperature and stirred for 2 days. The reaction was quenchedwith a saturated ammonium chloride and the crude product was extractedwith dichloromethane. The solvent was removed under reduced pressure andthe crude mixture was purified via column chromatography with silicagel, eluting with hexane/ethyl acetate (4/1) to give the title compound(86% yield). ¹H NMR (CDCl₃) δ 7.41 (m, 2H), 7.21 (m, 1H), 6.95 (dd,J=1.9, 8.5 Hz, 1H), 6.55 (dd, J=0.6, 2.2 Hz, 1H), 2.69 (t, J=7.5 Hz,2H), 2.43 (t, J=7.4 Hz, 2H), 2.09 (s, 3H), 1.96 (m, 2H), 1.71 (, 3H),1.13 (d, J=7.6 Hz, 9H). ¹³C NMR (CDCl₃) δ 209.1, 139.3, 132.6, 131.5,131.3, 122.2, 119.8, 113.6, 104.3, 42.9, 34.9, 29.6, 29.9, 25.7, 18.1,12.7.

e) 2-[3-(1-Triisopropylsilanyl-1H-indol-5-yl)-propyl]-[1,8]naphthyridineand2-Methyl-3-[2-(1-triisopropylsilanyl-1H-indol-5-yl)-ethyl]-[1,8]naphthyridine

A mixture of 5-(1-triisopropylsilanyl-1H-indol-5-yl)-pentan-2-one (1.10g, 3.07 mmol), 2-amino-pyridine-3-carbaldehyde (0.37 g, 3.07 mmol), andL-proline (0.18 g, 1.53 mmol) in ethanol (15 mL) was heated at refluxfor 24 h. The solvent was removed under reduced pressure to give a crudemixture which was purified via column chromatography, eluting withhexane/ethyl acetate (1/2) to give the two title compounds in a 2:1ratio.

2-[3-(1-Triisopropylsilanyl-1H-indol-5-yl)-propyl]-[1,8]naphthyridine(major isomer, 56% yield): ¹H NMR (CDCl₃) δ 9.08 (dd, J=2.0, 4.3 Hz,1H), 8.13 (dd, J=1.9, 8.0 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.37-7.45 (m,4H), 7.21 (d, J=3.2 Hz, 1H), 7.01 (dd, J=1.8 and 8.5, 1H), 6.54 (dd,J=0.6, 2.4 Hz, 1H), 3.11 (t, J=7.7 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.28(m, 2H), 1.69 (m, 3H), 1.13 (d, J=7.5 Hz, 18H). ¹³C NMR (CDCl₃) δ 166.6,155.8, 152.9, 139.2, 136.7, 136.5, 133.1, 131.5, 131.1, 122.4, 122.3,121.1, 120.8, 119.7, 113.5, 104.3, 38.8, 35.5, 31.4, 17.9, 12.6. MassSpectrum (LCMS, ESI) calculated for C₂₈H₃₈N_(3Si) 444.3 (M+H); found444.4.

2-Methyl-3-[2-(1-triisopropylsilanyl-1H-indol-5-yl)-ethyl]-[1,8]naphthyridine(minor isomer, 24% yield): ¹H NMR (CDCl₃) δ 9.01 (dd, J=1.9, 3.2 Hz,1H), 8.04 (dd, J=1.9, 8.1 Hz, 1H), 7.80 (s, 1H), 7.37-7.47 (m, 4H), 6.95(dd, J=1.6, 8.4 Hz, 1H), 6.56 (d, J=3.1 Hz, 1H), 3.07-3.18 (m, 4H), 2.81(s, 3H), 1.57-1.73 (m, 3H), 1.14 (d, J=7.6 Hz, 18H). ¹³C NMR (CDCl₃) δ162.4, 154.5, 152.2, 139.4, 135.9, 135.1, 135.0, 131.9, 131.5, 131.4,122.0, 121.3, 121.1, 119.6, 113.6, 104.2, 35.7, 35.1, 23.5, 17.9, 12.6.Mass Spectrum (LCMS, ESI) calculated for C₂₈H₃₈N_(3Si) 444.23 (M+H);found 444.4.

f) 3-{5-[2-(2-Methyl-[1,8]naphthyridin-3-yl)-ethyl]-indol-1-yl}-acrylicacid methyl ester

A mixture of2-methyl-3-[2-(1-triisopropylsilanyl-1H-indol-5-yl)-ethyl]-[1,8]naphthyridine(0.25 g, 0.74 mmol), propynoic acid methyl ester (0.07 g, 0.84 mmol),and tetrabutylammonium fluoride [1.0 M] (2.23 mL, 2.23 mmol) was stirredat room temperature overnight. The solvent was removed under reducedpressure to give a crude mixture which was purified via columnchromatography with silica gel, eluting with methylene chloride/methanol(95/5) to give the title compound (66% yield) as an E/Z isomericmixture. ¹H NMR (CDCl₃) δ 9.00 (m, 1H), 8.23 (s, 1H), 8.08 (m, 1H), 7.80(m, 1H), 7.50 (d, 1H). Mass Spectrum (LCMS, ESI) calculated forC₂₂H₂₂N₃O₂ 372.2 (M+H); found 372.2.

g)3-{5-[2-(2-Methyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-ethyl]-indol-1-yl}-propionicacid methyl ester

3-{5-[2-(2-Methyl-[1,8]naphthyridin-3-yl)-ethyl]-indol-1-yl}-acrylicacid methyl ester (230 mg, 6.1 mmol) was stirred in methanol (5 mL)under a hydrogen atmosphere in the presence of 10% palladium on carbon(10% w/w) (20 mg) for 3 days. After removal of solvent, the crudeproduct was purified by flash chromatography on silica gel withmethylene chloride/methanol (95/5) to give the title product (14 mg, 6%yield). ¹H NMR (CDCl₃) δ 7.40 (1H), 7.33 (1H), 7.23 (1H), 7.10 (1H),7.00 (d, 1H), 6.65 (br, 1H), 6.45 (1H), 4.45 (t, 2H), 3.67 (s, 3H), 3.40(br, 2H), 2.85 (4H), 2.30 (s, 3H), 2.70 (m, 2H), 1.90 (m, 2H). MassSpectrum (LCMS, ESI) calculated for C₂₃H₂₈N₃O₂ 378.2 (M+H); found 378.3.

h)3-{5-[2-(2-Methyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-ethyl]-indol-1-yl}-propionicacid

The title compound was synthesized from3-{5-[2-(2-methyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-ethyl]-indol-1-yl}-propionicacid methyl ester using the procedure described in Example 14, step (e),in 56% yield. ¹H NMR (CDCl₃) δ 7.34 (d, J=8.2 Hz, 1H), 7.25 (m, 1H),7.20 (m, 2H), 6.86 (m, 1H), 6.28 (d, J=2.8 Hz, 1H), 4.43 (t, J=7.0 Hz,2H), 3.39 (m, 2H), 2.85 (t, J=3.8 Hz, 2H), 2.79 (t, J=6.7 Hz, 2H), 2.68(m, 4H), 1.97 (s, 3H), 1.88 (m, 2H). Mass Spectrum (LCMS, ESI)calculated for C₂₂H₂₆N₃O₂ 364.2 (M+H); found 364.3.

EXAMPLE 493-{5-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionicacid

a) 2-[3-(1H-Indol-5-yl)-propyl]-[1,8]naphthyridine

Tetrabutylammonium fluoride [1.0 M in THF] (5.10 mL, 5.10 mmol) wasadded to a solution of2-[3-(1-triisopropylsilanyl-1H-indol-5-yl)-propyl]-[1,8]naphthyridine(1.14 g, 2.57 mmol) in THF (20 mL) at room temperature and stirred for 1h. The solvent was removed and the resulting crude product was purifiedvia column chromatography on silica gel, eluting with ethylacetate/hexane (2/1) to give the title product (100% yield). ¹H NMR(CDCl₃) δ 9.08 (dd, J=2.0, 4.3 Hz, 1H), 8.28 (br, 1H), 8.14 (dd, J=2.0,8.1, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J=8.3, 1H), 731(d, J=8.3 Hz, 1H), 7.18 (t, J=2.8 Hz, 1H), 7.05 (dd, J=1.6, 8.3 Hz, 1H),6.47 (m, 1H), 3.10 (t, J=7.8 Hz, 2H), 2.84 (t, J=7.7 Hz, 2H), 2.28 (m,2H). Mass Spectrum (LCMS, ESI) calculated for C₁₉H₁₈N₃ 288.2 (M+H);found 288.2.

b) 3-[5-(3-[1,8]Naphthyridin-2-yl-propyl)-indol-1-yl]-acrylic acidmethyl ester

The title compound was synthesized from2-[3-(1H-indol-5-yl)-propyl]-[1,8]naphthyridine using the proceduredescribed in Example 17, step (a), in 78% yield as an E/Z isomericmixture. Mass Spectrum (LCMS, ESI) calculated for C₂₃H₂₂N₃O₂ 372.2(M+H); found 372.3.

c) 3-[5-(3-[1,8]Naphthyridin-2-yl-propyl)-indol-1-yl]-propionic acidethyl ester

To a solution of 2-[3-(1H-indol-5-yl)-propyl]-[1,8]naphthyridine (0.180g, 0.627 mmol) in DMF (2 mL) was added sodium hydride (24.0 mg. 1.00mmol) at 0° C. The reaction mixture was warmed to room temperature andstirred for 2 h. After cooling to 0° C., 3-chloro-propionic acid ethylester (85.0 mg, 0.63 mmol) was added and stirred overnight at roomtemperature. Ice water was added and the resulting mixture was extractedwith methylene chloride. The combined organic layers were washed withwater and brine, and dried over Na₂SO₄. Chromatography of the crudeproduct on silica gel (methylene chloride/methanol, 95:5) gave the titleproduct (0.11 g, 45% yield). ¹H NMR (CDCl₃) δ 9.08 (d, 1H), 8.13 (d,1H), 8.08 (d, 1H), 7.30-7.50 (m, 4H), 7.10 (m, 2H), 6.40 (dd, 1H), 4.40(t, 2H), 4.10 (m, 2H), 3.10 (t, 2H), 2.80 (m, 4H), 2.25 (m, 2H), 1.20(q, 3H).

d)3-{5-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionicacid ethyl (and methyl)esters

3-[5-(3-[1,8]Naphthyridin-2-yl-propyl)-indol-1-yl]-propionic acid ethylester (0.11 g, 0.29 mmol) in methanol (5 mL) was stirred under hydrogenin the presence of 10% palladium on carbon (30.0 mg) for 24 h. Afterremoval of solvent, the crude product was used in next reaction withoutfurther purification.

For ethyl ester: ¹H NMR (CDCl₃) δ 7.42 (s, 1H), 7.24 (d, J=8.2 Hz, 2H),7.05 (m, 2H), 6.39 (d, J=2.9, 1H), 6.34 (d, J=7.4 Hz, 1H), 4.90 (br,1H), 4.41 (t, J=6.8 Hz, 2H), 4.11 (m, 4H), 3.37 (m, 2H), 2.58-2.80 (m,6H), 2.03 (m, 2H), 1.88 (m, 2H), 1.29 (m, 3H).

For methyl ester: Mass Spectrum (LCMS, ESI) calculated for C₂₃H₂₈N₃O₂378.3 (M+H); found 378.3.

e)3-{5-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionicacid

A mixture of3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionicacid ethyl (or methyl) esters (0.10 g, 0.26 mmol) and sodium hydroxide(0.06 g, 1.58 mmol) in tetrahydrofuran/water (7.5 mL, 3:1) was stirredat room temperature for 3 days. After neutralizing with 1.0 N HCl, thecrude product was extracted with ethyl acetate and purified via columnchromatography (methylene chloride/methanol) (95:5) to give the titlecompound as a white solid (49% yield). ¹H NMR (CDCl₃) δ 13.97 (br, 1H),8.98 (br, 1H), 7.38 (d, J=7.3 Hz, 1H), 7.34 (d, J=1.1 Hz, 1H), 7.18 (m,1H), 7.02 (dd, J=1.6 and 8.4 Hz, 1H), 6.44 (d, J=7.4 Hz, 1H), 6.36 (dd,J=0.6, 4.0 Hz, 1H), 4.39 (t, J=6.7 Hz, 2H), 3.38 (m, 2H), 2.79 (m, 6H),1.99 (m, 4H), 1.83 (m, 2H). Mass Spectrum (LCMS, ESI) calculated forC₂₂H₂₆N₃O₂ 364.2 (M+H); found 364.3.

EXAMPLE 503-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-hexanoicacid

a) 3-[5-(3-[1,8]Naphthyridin-2-yl-propyl)-indol-1-yl]-hexanoic acidethyl ester

To a solution of 2-[3-(1H-indol-5-yl)-propyl]-[1,8]naphthyridine (0.18g, 0.62 mmol) in DMF (2 mL) was added sodium hydride (30.0 mg, 1.24mmol) at room temperature. After stirring for 15 minutes,3-bromo-hexanoic acid ethyl ester (276 mg, 1.24 mmol) was added. Thereaction mixture was stirred overnight and quenched with water. Thecrude product was extracted with methylene chloride, washed with brine,and purified via column chromatography with silica gel (ethylacetate/hexane1:1), to give the title product (17% yield). ¹H NMR(CDCl₃) δ 9.08 (dd, J=1.7, 4.0 Hz, 1H), 8.14 (m, 1H), 8.06 (m, 1H),7.32-7.44 (m, 4H), 7.05-7.12 (m, 2H), 6.45 (d, J=3.2 Hz, 1H), 4.81 (m,1H), 3.99 (m, 2H), 3.08 (m, 2H), 2.83 (m, 4H), 2.22 (m, 2H), 1.90 (m,2H), 1.20 (m, 2H), 1.07 (m, 3H), 0.87 (m, 3H). Mass Spectrum (LCMS, ESI)calculated for C₂₇H₃₂N₃O₂ 430.3 (M+H); found 430.3.

b)3-{5-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-hexanoicacid ethyl ester

A mixture of 3-[5-(3-[1,8]naphthyridin-2-yl-propyl)-indol-1-yl]-hexanoicacid ethyl ester (100 mg, 0.665 mmol) and 10% palladium on carbon (30mg) in methanol (5 mL) was stirred under hydrogen for 2 days. Thereaction solution was filtered through celite and dried to give thecrude product, which was purified via column chromatography eluting withhexane/ethyl acetate (4/1), to give the title compound (80% yield). ¹HNMR (CDCl₃) δ 7.39 (d, J=0.9 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.02-7.10(m, 3H), 6.44 (dd, J=3.6, 6.3 Hz, 1H), 6.33 (d, J=7.3 Hz, 1H), 5.60 (br,1H), 4.82 (m, 1H), 3.97 (q, 2H), 3.35 (t, 2H), 2.60-2.80 (m, 8H),1.80-2.10 (m, 6H), 1.20 (m, 2H), 1.11 (m, 3H), 0.87 (m, 3H). MassSpectrum (LCMS, ESI) calculated for C₂₇H₃₆N₃O₂ 434.3 (M+H); found 434.4.

c)3-{5-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-hexanoicacid

A mixture of3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-hexanoicacid ethyl ester (83.0 mg, 0.218 mmol) and NaOH (52.0 mg, 1.31 mmol) inTHF/H₂O (3:1) was stirred at room temperature for 2 days. Aqueous HClsolution (1 N) was added to adjust the pH to 4-5. The crude product wasextracted with ethyl acetate, and the combined organic layers werewashed with brine and dried over Na₂SO₄. Removal of solvent gave thecrude product, which was purified via column chromatography, elutingwith 5% methanol in methylene chloride, to give the title compound (65%yield). ¹H NMR (CDCl₃) δ 9.35 (br, 1H), 7.42 (d, J=8.1 Hz, 1H) 7.27 (m,H), 7.16-7.20 (m, 2H), 6.95 (d, J=7.9 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H),6.22 (d, J=7.2 Hz, 1H), 4.91 (br, 1H), 3.40 (m, 2H), 2.56-2.82 (m, 10H),1.84-2.05 (m, 6H), 0.86 (m, 3H). Mass Spectrum (LCMS, ESI) calculatedfor C₂₅H₃₂N₃O₂ 406.3 (M+H); found 406.4.

EXAMPLE 513-Phenyl-3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionicacid

a) 3-[5-(3-[1,8]Naphthyridin-2-yl-propyl)-indol-1-yl]-3-phenyl-acrylicacid ethyl ester

A mixture of2-[3-(1-triisopropylsilanyl-1H-indol-5-yl)-propyl]-[1,8]naphthyridine(125 mg, 0.282 mmol), phenyl-propynoic acid ethyl ester (98.0 mg, 0.563mmol), and tetrabutylammonium fluoride [1.0 M] 0.85 mL, 0.85 mmol) inTHF (3 mL) was stirred for 24 h. After removal of the solvent, the crudereaction mixture was purified via column chromatography on silica gelwith ethyl acetate/hexane (2:1) to give the title product as an E/Zisomeric mixture in 64% yield. Mass Spectrum (LCMS, ESI) calculated forC₃₀H₂₈N₃O₂ 462.2 (M+H); found 462.3.

b).3-Phenyl-3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionicacid ethyl ester

3-[5-(3-[1,8]Naphthyridin-2-yl-propyl)-indol-1-yl]-3-phenyl-acrylic acidethyl ester (30.0 mg, 0.484 mmol) in methanol (2 mL) was stirred underhydrogen in the presence of 10% palladium on carbon (15.0 mg) at roomtemperature for 3 days. Then, the reaction mixture was filtered throughcelite and purified via column chromatography on silica gel (methylenechloride/methanol) (95/5) to give the title product as yellow oil (20.0mg, 66% yield). ¹H NMR (CDCl₃) δ 8.2 (d, 1H), 8.0 (m, 1H), 7.45 (m, 2H),7.27 (m, 2H), 6.9-7.2 (m, 4H), 6.5 (1H), 6.3 (1H), 6.20 (m, 1H), 6.10(m, 1H), 4.15 (m, 2H), 3.4 (m, 2H), 3.3 (m, 4H), 2.6 (m, 4H), 2.1 (m,2H), 1.89 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C₃₀H₃₄N₃O₂468.27 (M+H); found 468.3.

c)3-Phenyl-3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionicacid

A mixture of3-phenyl-3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-propionicacid ethyl ester (0.020 g, 0.04 mmol) and sodium hydroxide (0.01 g, 0.25mmol) in THF/H₂O [1/0.3] (1.3 mL) was stirred at 50° C. for 24 h. Thereaction mixture was neutralized with 1.0 N HCl to pH 5 and extractedwith ethyl acetate. After removal of solvent, the crude product waspurified via column chromatography, eluting with methylenechloride/methanol (95/5) to give the title compound (15% yield) as whitesolid. ¹H NMR (CDCl₃) δ 10.76 (br, 1H), 8.16 (br, 1H), 7.57 (br, 1H),7.10-7.45 (m, 8H), 7.03 (m, 1H), 6.95 (m, 2H), 6.18 (m, 1H), 3.38 (m,2H), 3.21 (m, 2H), 2.61 (m, 2H), 2.43 (m, 2H), 2.03 (m, 2H), 1.82 (m2H), 1.70 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C₂₈H₃₀N₃O₂440.2 (M+H); found 440.3.

d)3-Phenyl-3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-acrylicacid

The title compound was synthesized from3-[5-(3-[1,8]naphthyridin-2-yl-propyl)-indol-1-yl]-3-phenyl-acrylic acidethyl ester using the procedures described in Example 50, step (b)(isolated as a minor product) and step (c), in 10% yield as an E/Zisomeric mixture. ¹H NMR (CDCl₃) δ 7.10-7.35 (m, 7H), 7.00 (m, 1H), 6.92(d, J=3.3 Hz, 1H), 6.46 (d, J=3.3 Hz, 1H), 6.31 (s, 1H), 6.22 (d, J=7.3Hz, 1H), 6.13 (m, 1H), 3.37 (m, 2H), 2.64 (m, 2H), 2.56 (m, 2H), 2.47(m, 2H), 2.04 (m, 2H), 1.84 (m, 2H). Mass Spectrum (LCMS, ESI)calculated for C₂₈H₂₈N₃O₂ 437.3 (M+H); found: 438.4.

EXAMPLE 523-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-propionicacid

a) 3-Bromo-5-(2,2,2-trifluoro-ethoxy)-pyridine

To a slurry of sodium hydride (60% dispersion in mineral oil, 0.54 g, 14mmol) in DMF (15 mL) was added commercially available2,2,2-trifluoroethanol (0.97 mL, 14 mmol) at room temperature. Afterstirring for 15 minutes, a solution of 3,5-dibromopyridine (3.2 g, 14mmol) in 5 mL of DMF was added dropwise. The reaction mixture was heatedovernight at 70° C. After cooling to room temperature, the reaction wasdiluted with water and extracted with ethyl acetate. The extracts weredried over magnesium sulfate and the solvent was removed under reducedpressure. The crude product was chromatographed on silica (5% ethylacetate/hexanes) to give the title compound (1.6 g, 46% yield) as clearoil. ¹H NMR (CDCl₃) δ 8.42 (d, 1H, J=1.7 Hz), 8.32 (d, 1H, J=2.5 Hz),7.46 (m, 1H), 4.42 (m, 2H).

b) 3-Triethoxyprop-1-ynyl-5-(2,2,2-trifluor-ethoxy)-pyridine

The title compound was synthesized from3-bromo-5-(2,2,2-trifluoro-ethoxy)-pyridine and 3,3,3-triethoxypropyneusing the procedure described in Example 43, step (e), in 46% yield. ¹HNMR (CDCl₃) δ 8.44 (bs, 1H), 8.35 (bs, 1H), 7.34 (m, 1H), 4.40 (q, 2H,J=7.9 Hz), 3.76 (q, 6H, J=7.1 Hz), 1.28 (t, 9H, J=7.1 Hz).

c) [5-(2,2,2-Trifluoro-ethoxy)-pyridin-3-yl]-propynoic acid ethyl ester

The title compound was synthesized from3-triethoxyprop-1-ynyl-5-(2,2,2-trifluor-ethoxy)-pyridine using theprocedure described in Example 43, step (f), in 100% yield. ¹H NMR(CDCl₃) δ 8.55 (bs, 1H), 8.48 (bs, 1H), 7.43 (m, 1H), 4.43 (q, 2H, J=7.9Hz), 4.33 (q, 2H, J=7.2 Hz), 1.38 (t, 3H, J=7.2 Hz).

d)7-[2-(1-{2-Ethoxycarbonyl-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-vinyl}-1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyrdine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester and[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-propynoic acid ethyl esterusing the procedure described in Example 16, step (d1), in 79% yield asan E/Z isomeric mixture. ¹H NMR (CDCl₃) δ 8.47 (d, 0.33H, J=2.6 Hz),8.42 (d, 0.67H, J=2.6 Hz), 8.36 (bs, 1H), 7.31 (d, 1H, J=7.8 Hz), 7.23(m, 0.33H), 7.16 (d, 0.33H, J=9.1 Hz), 7.12 (m, 0.67H), 7.09 (d, 0.33H,J=2.6 Hz), 7.02 (d, 0.67H, J=3.3 Hz), 6.99 (m, 0.67H), 6.93 (d, 1H,J=7.8 Hz), 6.83, (m, 1H), 6.74 (m, 0.67H), 6.59 (d, 0.67H, J=3.3 Hz),6.52 (dd, 0.67H, J=0.48, 2.8 Hz), 6.26 (s, 0.33H), 6.25 (s, 0.67H), 4.35(m, 4H), 4.11 (m, 2H), 3.75 (m, 2H), 3.20 (m, 2H), 2.73 (t, 2H, J=6.5Hz), 1.92 (m, 2H), 1.52 (s, 9H), 1.19 (t, 1H, J=7.0 Hz), 1.03 (t, 2H,J=7.2 Hz).

e)7-[2-(1-{2-Ethoxycarbonyl-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-ethyl}-1H-indol-5-yloxy)-ethyl-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-[2-(1-{2-ethoxycarbonyl-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-vinyl}-1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyrdine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 59% yield. ¹H NMR (CDCl₃) δ 8.27 (bs, 1H), 8.23 (bs, 1H), 7.30(d, 1H, J=7.6 Hz), 7.16 (m, 2H), 7.09 (d, 1H, J=2.3 Hz), 6.92 (m, 2H),6.82 (dd, 1H, J=2.3, 6.5 Hz), 6.47 (d, 1H, J=3.3 Hz), 6.02 (t, 1H, J=7.4Hz), 4.35 (t, 2H, J=7.0 Hz), 4.09 (m, 4H), 3.74 (m, 2H), 3.18 (t, 2H,J=7.0 Hz), 2.71 (t, 2H, J=6.5 Hz), 1.91 (m, 2H), 1.50 (s, 9H), 1.11 (t,3H, J=7.0 Hz).

f)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-propionicacid ethyl ester

The title compound was synthesized from7-[2-(1-{2-ethoxycarbonyl-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-ethyl}-1H-indol-5-yloxy)-ethyl-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 71% yield. ¹H NMR (CDCl₃) δ 8.26 (bs, 1H), 8.24 (bs, 1H), 7.13(m, 4H), 6.92 (m, 1H), 6.81 (dd, 1H, J=2.3, 6.5 Hz), 6.48 (m, 2H), 6.03(t, 1H, J=7.4 Hz), 5.35 (bs, 1H), 4.27 (m, 4H), 4.06 (m, 2H), 3.34 (m,2H), 3.28 (t, 2H, J=9.0 Hz), 3.05 (t, 2H, J=6.7 Hz), 2.68 (t, 2H, J=6.2Hz), 1.88 (m, 2H), 1.12 (t, 3H, J=7.2 Hz).

g)3-{5-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-propionicacid

The title compound was synthesized from3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-3-[5-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 56% yield. ¹H NMR (DMSO-d₆) δ 8.27 (s, 1H), 8.25 (s, 1H), 7.70 (d,1H, J=3.3 Hz), 7.58 (m, 1H), 7.48 (d, 1H, J=9.0 Hz), 7.03 (d, 1H, J=7.2Hz), 7.00 (d, 1H, J=2.6 Hz), 6.69 (dd, 1H, J=2.3, 6.5 Hz), 6.37 (d, 1H,J=3.0 Hz), 6.34 (d, 1H, J=7.2 Hz), 6.31 (bs, 1H), 5.98 (m, 1H), 4.82 (q,2H, J=8.8 Hz), 4.17 (t, 2H, J=6.7 Hz), 3.55 (m, 2H), 3.21 (m, 2H), 2.85(t, 2H, J=6.7 Hz), 2.58 (t, 2H, J=6.2 Hz), 1.73 (m, 2H). ¹⁹F NMR(DMSO-d₆) δ −73.05 (t, 3F, J=8.8 Hz). Mass Spectrum (LCMS, ESI)calculated for C₂₈H₂₈F₃N₄O₄: 541.2 (M+1); found: 541.3.

EXAMPLE 533-(5-ethoxy-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) 3-Bromo-5-ethoxy-pyridine

The title compound was synthesized from 3,5-dibromopyridine and ethanolusing the procedure described in Example 53, step (a) in 60% yield. ¹HNMR (CDCl₃) δ 8.27 (bs, 1H), 8.23 (bs, 1H), 7.33 (m, 1H), 4.06 (q, 2H,J=7.0 Hz), 1.43 (t, 3H, J=7.0 Hz).

b) 3-Ethoxy-5-triethoxyprop-1-ynyl-pyridine

The title compound was synthesized from 3-bromo-5-ethoxy-pyridine and3,3,3-triethoxypropyne using the procedure described in Example 43, step(e), in 37% yield. ¹H NMR (CDCl₃) δ 8.27 (bs, 1H), 8.24 (bs, 1H), 7.21(m, 1H), 4.02 (q, 2H, J=7.0 Hz), 3.72 (q, 6H, J=7.0 Hz), 1.39 (t, 3H,J=7.0 Hz), 1.23 (t, 9H, J=7.0 Hz).

c) (5-Ethoxy-pyridin-3-yl)-propynoic acid ethyl ester

The title compound was synthesized from3-ethoxy-5-triethoxyprop-1-ynyl-pyridine using the procedure describedin Example 43, step (f), in 96% yield. ¹H NMR (CDCl₃) δ 8.40 (d, 1H,J=1.4 Hz), 8.35 (d, 1H, J=2.8 Hz), 7.33 (m, 1H), 4.32 (q, 2H, J=7.0 Hz),4.08 (q, 2H, J=7.0 Hz), 1.46 (t, 3H, J=7.0), 1.38 (t, 3H, J=7.0 Hz).

d)7-(2-{1-[2-Ethoxycarbonyl-1-(5-ethoxy-pyridin-3-yl)-vinyl-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from(5-ethoxy-pyridin-3-yl)-propynoic acid ethyl ester and7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(dl), in 70% yield. Mass Spectrum (LCMS, ESI) calculated for C₃₅H₄₀N₄O₆:513.2 (M-Boc+H); found: 513.3 (-Boc).

e)7-(2-{1-[2-Ethoxycarbonyl-1-(5-ethoxy-pyridin-3-yl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(5-ethoxy-pyridin-3-yl)-vinyl-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 60% yield. ¹H NMR (CDCl₃) δ 8.19 (bs, 1H), 8.18 (bs, 1H), 7.31(d, 1H, J=7.8 Hz), 7.19 (m, 2H), 7.10 (d, 1H, J=2.3 Hz), 6.95 (d, 1H,J=7.6 Hz), 6.84 (m, 2H), 6.47 (d, 1H, J=7.4 Hz), 6.03 (t, 1H, J=7.4 Hz),4.38 (t, 2H, J=7.0 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.95 (q, 2H, 7.0 Hz),3.76 (m, 2H), 3.30 (t, 2H, J=8.3 Hz), 3.21 (t, 2H, J=7.0 Hz), 2.72 (t,2H, J=8.3 Hz), 1.92 (m, 2H), 1.52 (s, 9H), 1.36 (t, 3H, J=7.0 Hz), 1.12(t, 3H, J=7.2 Hz).

f)3-(5-Ethoxy-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy-indol-1-yl}-propionicacid ethyl ester

The title compound was synthesized from7-(2-{1-[2-ethoxycarbonyl-1-(5-ethoxy-pyridin-3-yl)-ethyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(f), in 71% yield. ¹H NMR (CDCl₃) δ 8.19 (bs, 1H), 8.16 (bs, 1H), 7.19(m, 3H), 7.08 (d, 1H, J=2.3 Hz), 6.87 (t, 1H, J=2.0 Hz), 6.81 (dd, 1H,J=2.3, 6.5 Hz), 6.51 (d, 1H, J=7.4 Hz), 6.47 (1H, J=3.3 Hz), 6.05 (bs,1H), 6.02 (t, 1H, J=7.7 Hz), 4.29 (t, 2H, J=6.5 Hz), 4.06 (q, 2H, J=7.2Hz), 3.95 (q, 2H, J=7.0 Hz), 3.43 (m, 2H), 3.29 (t, 2H, J=8.3 Hz),3.08(t, 2H, J=6.5 Hz), 2.71 (t, 2H, J=6.3 Hz), 1.91 (m, 2H), 1.36 (t,3H, J=7.0 Hz), 1.13 (t, 3H, J=7.2 Hz).

g)3-(5-Ethoxy-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy-indol-1-yl}-propionicacid

The title compound was synthesized from3-(5-ethoxy-pyridin-3-yl)-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 18, step (g),in 69% yield. ¹H NMR (DMSO-d₆) δ 8.18 (bs, 1H), 8.13 (bs, 1H), 7.73 (d,1H, J=3.0 Hz), 7.48 (d, 1H, J=9.0 Hz), 7.35 (s, 1H), 7.13 (m, 1H), 7.02(d, 1H, J=2.3 Hz), 6.71 (dd, 1H, J=2.0, 7.0 Hz), 6.53 (bs, 1H), 6.41 (m,2H), 5.99 (t, 1H, J=7.0 Hz), 4.20 (t, 2H, J=7.0 Hz), 4.05 (m, 2H), 3.49(m, 4H), 2.90 (t, 2H, J=6.0 Hz), 2.62 (t, 2H, J=6.0 Hz), 1.75 (m, 2H),1.29 (t, 3H, J=7.0 Hz). Mass Spectrum (LCMS, ESI) calculated forC₂₈H₃₁N₄O₄: 487.2 (M+1); found: 487.3.

EXAMPLE 543-Pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

a) Pyridin-4-yl-propynoic acid ethyl ester

The title compound is prepared from commercially available material3-oxo-3-pyridin-4-yl-propionic acid ethyl ester using the proceduredescribed in Example 32, step (b), in 74% yield. ¹H NMR (CDCl₃) δ 8.69(m, 2H), 7.43 (m, 2H), 4.32 (q, 2H), 1.45 (t, 3H).

b)7-{2-[1-(2-Ethoxycarbonyl-1-pyridin-4-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound is prepared from pyridin-4-yl-propynoic acid ethylester and7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 17, step(a), in 64% yield as an E/Z mixture. The mixture is used for the nextreaction without further separation.

c)7-{2-[1-(2-Ethoxycarbonyl-1-pyridin-4-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester

The title compound is synthesized from7-{2-[1-(2-Ethoxycarbonyl-1-pyridin-4-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 18, step(e), in 43% yield. ¹H NMR (CDCl₃) δ 8.53 (d, 2H), 7.35 (m, 1H), 7.28 (m,1H), 7.13 (m, 2H), 7.02 (d, 2H), 6.96 (m, 1H), 6.84 (m, 1H), 6.50 (m,1H), 6.00 (t, 1H), 4.40 (t, 2H), 4.10 (q, 2H), 3.77 (t, 2H), 3.32(m,2H), 3.25 (m, 2H), 2.75 (m, 2H), 1.92 (m, 2H), 1.52 (s, 9H), 1.15 (t,3H). Mass Spectrum (LCMS, ESI) calculated for C₃₃H₃₉N₄O₅ 571.29 (M+H);found 471.4 (M-Boc+H, 100%).

d)3-Pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester

The title compound is synthesized from7-{2-[1-(2-Ethoxycarbonyl-1-pyridin-4-yl-ethyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(e), in 36% yield. ¹H NMR (CDCl₃) δ 8.52 (d, 2H), 7.16 (d, 1H), 7.10 (m,2H), 7.00 (d, 1H), 6.83 (m, 1H), 6.48 (m, 2H), 6.00 (m, 1H), 4.30 (m,2H), 4.12 (m, 2H), 3.40 (m, 2H), 3.28 (m, 2H), 3.05 (m, 2H), 2.70 (m,2H), 1.90 (m, 2H), 1.20 (t, 3H). Mass Spectrum (LCMS, ESI) calculatedfor C₂₈H₃₁N₄O₃ 471.24 (M+H); found 471.3.

e)3-Pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid

The title compound is synthesized from3-pyridin-4-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-propionicacid ethyl ester using the procedure described in Example 16, step (f),in 66% yield. ¹H NMR (CDCl₃) δ 8.44 (br, 2H), 7.38 (m, 1H), 7.20 (d,1H), 7.18 (d, 1H), 7.15 (m, 1H), 7.02 (m, 1H), 6.65 (dd, 1H), 6.49 (m,1H), 6.35 (m, 1H), 6.10 (m, 1H), 3.70 (m, 4H), 3.38 (m, 2H), 3.20 (m,2H), 2.67 (m, 2H), 1.85 (m, 2H). Mass Spectrum (LCMS, ESI) calculatedfor C₂₆H₂₇N₄O₃ 443.21 (M+H); found 443.2.

EXAMPLE 553-Pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylicacid

a)3-Pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylicacid ethyl ester

The title compound is prepared from7-{2-[1-(2-Ethoxycarbonyl-1-pyridin-2-yl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylicacid tert-butyl ester using the procedure described in Example 16, step(e), in 74% yield. ¹H NMR (CDCl₃) δ 8.50 (d, 1H), 8.0 (s, 1H), 7.77 (t,1H), 7.45 (m, 1H), 7.10 (d, 2H), 7.00 (d, 1H), 6.90 (d, 1H), 6.78 (dd,1H), 6.60 (m, 1H), 6.50 (d, 1H), 6.30 (s, 1H), 4.90 (br, 1H), 4.30 (t,d, 2H), 4.13 (m, 2H), 3.40 (m, 2H), 3.10 (t, 2H), 2.70 (t, 2H), 1.90 (m,2H), 1.15 (t, 3H).

b)3-Pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylicacid

The title compound is prepared from3-pyridin-2-yl-3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-acrylicacid ethyl ester using the procedure described in Example 16, step (f),in 54% yield. ¹H NMR (CDCl₃) δ 8.9 (br, 1H), 8.6 (m, 1H), 7.60 (m, 1H),7.25 (m, 2H), 7.20 (d, 1H), 7.08 (m, 2H), 6.98 (m, 1H), 6.72 (m, 1H),6.50 (m, 2H), 6.42 (d, 1H), 4.20 (m, 2H), 3.40 (m, 2H), 2.95 (m, 2H),2.70 (m, 2H), 1.90 (2H). Mass Spectrum (LCMS, ESI) calculated forC₂₆H₂₄N₄O₃ 440.27 (M+H); found 441.3.

EXAMPLE 56 Preparation of6-(2-hydroxy-ethyl)-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylicacid tert-butyl ester

a) 2-Amino-6-methyl-pyridin-3-ol

A mixture of 6-methyl-2-nitro-pyridin-3-ol (18.5 g, 0.120 mmol), 10%palladium on activated carbon (1.35 g), and ethyl acetate (240 mL) washydrogenated for 3 days. The mixture was filtered through Celite andwashed with methanol/ethylacetate (5%). The filtrate and washing werecombined and concentrated to give the title compound (14.7 g, 99% yield)as a pale brown solid. ¹H NMR (DMSO-d₆) δ 9.19 (bs, 1H), 6.73 (d, 1H,J=7.6 Hz), 6.12 (d, 1H, J=7.6 Hz), 5.36 (bs, 2H), 2.15 (s, 3H).

b) 6-Methyl-4H-pyrido[3,2-b][1,4]oxazin-3-one L. Savelon, et. al,Bioorganic & Medicinal Chemistry, 6, 133, (1998)

To a suspension of 2-amino-6-methyl-pyridin-3-ol (18.3 g, 148 mmol),sodium bicarbonate (30 g, 354 mmol), H₂O (100 mL), and 2-butanone (100mL) in an ice-water bath was added a solution of chloroacetyl chloride(13.3 mL. 167 mmol) in 2-butanone (30 mL) over 1.5 h, controlling thetemperature below 10° C. After the addition was complete, the ice-waterbath was removed and the mixture was stirred at ambient temperature for30 minutes, followed by refluxing for 1.5 h. The solvents wereevaporated, and the resulting solid washed with H₂O (3 times), and driedunder high vacuum overnight, giving the title compound (19.2 g, 79%yield) as a pale yellow solid. ¹H NMR (CDCl₃) δ 10.45 (bs, 1H), 7.17 (d,1H, J=8.1 Hz), 6.78 (d, 1H, J=8.1 Hz), 4.62 (s, 2H), 2.52 (s, 3H). Massspectrum (LCMS, ESI) calculated for C₈H₉N₂O₂ 165.1 (M+1); found 165.1.

c) 6-Methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

A flask was charged with lithium aluminum hydride (607 mg, 16.0 mmol)was placed in an ice-water bath under an argon atmosphere. THF (13 mL)was added slowly. To this suspension was added slowly a solution of6-methyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.05 g, 6.40 mmol) in THF(13 mL). After the addition was completed, additional THF (9 mL) wasadded, and the reaction was stirred in the ice-water bath for 30minutes. Ice-water bath was removed, the mixture was stirred at ambienttemperature for 3 h. The mixture was cooled with an ice-water bath, andH₂O (0.86 mL) was added slowly, followed by cooled aqueous NaOH solution(0.64 mL, 10%). The ice-water bath was removed, additional H₂O (1.8 mL)was added. After stirring for 30 minutes, Celite and Na₂SO₄ were added.The mixture was filtered through Celite, and the Celite washed withEtOAc. The filtrate and the washing were combined, dried over Na₂SO₄,and concentrated to give the title compound (0.96 g, quantitative yield)as a while solid. ¹H NMR(CDCl₃) δ 6.85 (d, 1H, J=8.0 Hz), 6.35 (d, 1H,J=8.0 Hz), 6.08 (bs, 1H), 4.19-4.16 (m, 2H), 3.54-3.52 (m, 2H), 2.31 (s,3H).

d) 6-Methyl-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylic acidtert-butyl ester

A mixture of 6-methyl-3,4-dihydro-2h-pyrido[3,2-b][1,4]oxazine (0.89 g,5.93 mmol) and di-tert-butyl dicarbonate was heated and stirred at 60°c. for 48 h, and then allowed to cooled to ambient temperature to givecrude product. Recrystallization of the crude product from hexane gavethe title compound (118 g, 80% yield) as a white solid. This crudeproduct was used in next step reaction without further purification.

e)6-tert-Butoxycarbonylmethyl-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylicacid tert-butylester

To a solution of diisopropylamine (1.23 ml, 8.80 mmol) in thf (8.0 ml)at −78° c. was added n-butyllithium (3.26 ml, 2.5 m in hexanes) andstirred for 20 min. To the above solution was added a solution of6-tert-butoxycarbonylmethyl-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylicacid tert-butylester (1.1 g, 4.40 mmol) in thf (15 ml) over a period of30 min. After the addition completed, the mixture was stirred for 40min. Diethylcarbonate (0.85 ml, 7.04 mmol) was added at once and stirredfor 15 min. Dry ice-acetone bath was removed. The mixture was stirred inan ice water bath for 1 h. Saturated NH₄Cl was added. The mixture wasdiluted with ethyl acetate. The organic layer was separated, washed withh₂O, brine, dried over na₂so₄, concentrated, and flash chromatographedon silica gel, eluting with ethyl acetate/hexane (5, 10, 15, 25, 30%) togive the title compound (755 mg, 49% yield) as a yellow oil. ¹HNMR(CDCl₃) δ 7.13 (d, 1H, j=8.2 Hz), 6.97 (d, 1H, j=8.2 Hz), 4.23 (t,2H, j=4.4 Hz), 3.89 (t, 2H, j=4.5 Hz), 3.65 (s, 2H), 1.54 (s, 9H), 1.45(s, 9H).

f) 2-(3,4-dihydro-2h-pyrido[3,2-b][1,4]oxazin-6-yl)-ethanol

To a solution of6-tert-butoxycarbonylmethyl-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylicacid tert-butyl ester (350 mg, 1 mmol) in THF (4.0 ml) was added asolution of lithium borohydride (0.6 ml, 2.0 m in thf). The mixture wasrefluxed overnight, then cooled in an ice-bath. Aqueous solution of naoh(0.36 ml, 5%) was added. The ice-bath was removed. Additional h₂O (0.36ml) was added and the mixture stirred for 10 min. Celite and na₂so₄ wereadded. The mixture was filtered through celite, and the celite washedwith etoac. The filtrate and washing were combined, dried over na₂so₄,concentrated, and flash chromatographed on silica gel, eluting withmeoh/dcm (1, 2, 3, 4%) to give the product (171 mg, 94% yield) as ayellow oil. ¹H NMR(CDCl₃) δ6.90 (d, 1H, J=7.8 Hz), 6.39 (d, 1H, J=7.7Hz), 4.85 (bs, 1H), 4.20 (t, 2H, J=4.4 Hz), 3.91 (t, 2H, J=5.5 Hz),3.69-3.52 (m, 2H), 2.78 (t, 2H, J=5.6 Hz).

EXAMPLE 57 In Vitro Inhibition of Purified Enzymes

Fibrinogen-IIb-IIIa Assay

The assay is based on the method of Dennis (Dennis, M. S., et al.,Proteins 15: 312-321 (1993)). Costar 9018 flat-bottom 96-well ELISAplates were coated overnight at 4□C with 100 μL/well of 10 μg/mL humanfibrinogen (Calbiochem 341578) in 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 2mM CaCl₂, 0.02% NaN₃ (TAC buffer), and blocked for 1 hr at 37□C with 150μL/well of TAC buffer containing 0.05% Tween 20 and 1% bovine serumalbumin (TACTB buffer). After washing 3 times with 200 μL/well of 10 mMNa₂ HPO₄ pH 7.5, 150 mM NaCl, 0.01% Tween 20 (PBST buffer), controls ortest compound (0.027-20.0 μM) were mixed with 40 μg/mL human GPIIbIIIa(Enzyme Research Laboratories) in TACTB buffer, and 100 μL/well of thesesolutions were incubated for 1 hr at 37° C. The plate was then washed 5times with PBST buffer, and 100 μL/well of a monoclonal anti-GPIIbIIIaantibody in TACTB buffer (1 μg/mL, Enzyme Research LaboratoriesMabGP2b3a) was incubated at 37□C for 1 hr. After washing (5 times withPBST buffer), 100 μL/well of goat anti-mouse IgG conjugated tohorseradish peroxidase (Kirkegaard & Perry 14-23-06) was incubated at37° C. for 1 hr (25 ng/mL in PBST buffer), followed by a 6-fold PBSTbuffer wash. The plate was developed by adding 100 μL/well of 0.67 mgo-phenylenediamine dihydrochloride per mL of 0.012% H₂O₂, 22 mM sodiumcitrate, 50 mM sodium phosphate, pH 5.0 at room temperature. Thereaction was stopped with 50 μL/well of 2M H₂SO₄, and the absorbence at492 nm was recorded. Percent (%) inhibition was calculated from theaverage of three separate determinations relative to buffer controls (notest compound added), and a four parameter fit (Marquardt, D. W., J.Soc. Indust. Appl Math. 11:431-441 (1963)) was used to estimate the halfmaximal inhibition concentration (IC₅₀).

α_(v)β₃-Vitronectin Assay

The assay was based on the method of Niiya (Niiya, K., et al., Blood70:475-483 (1987)). Costar 9018 flat-bottom 96-well ELISA plates werecoated overnight at room temperature with 100 μL/well of 0.4 μg/mL humanα_(v)β₃ (Chemicon CC1019) in TS buffer (20 mM Tris-HCl pH 7.5, 150 mMNaCl, 1 mM CaCl₂, 1 mM MgCl₂, 1 mM MnCl₂). All subsequent steps wereperformed at room temperature. Plates were blocked for 2 hr with 150μL/well of TS buffer containing 1% BSA (TSB buffer), and washed 3 timeswith 200 μL/well of PBST buffer. Controls or test compound (0.0001-20.0μM) were mixed with 1 μg/mL of human vitronectin (Chemicon CC080) thathad been biotinylated in-house with sulfo-NHS-LC-LC-biotin (Pierce21338, 20:1 molar ratio), and 100 μL/well of these solutions (in TSBbuffer) were incubated for 2 hr. The plate was then washed 5 times withPBST buffer, and 100 μL/well of 0.25 μg/mL NeutrAvidin-horseradishperoxidase conjugate (Pierce 31001) in TSB buffer was incubated for 1hr. Following a 5-fold PBST buffer wash, the plate was developed andresults were calculated as described for the fibrinogen-IIbIIIa assay.IC₅₀ values for inhibition of the α_(v)β₃-vitronectin interaction byother compounds of the invention are presented in Table 1. TABLE 1 InVitro Activity of New A_(v)B₃ Antagonists Example # IC₅₀ (nM) 1 500 4670 5 50 7 500 14 4.00 15 6.00 38 0.24α_(v)β₅-Vitronectin Assay

The assay is similar to the α_(v)β₃-vitronectin assay. Costar 9018flat-bottom 96-well ELISA plates were coated overnight at roomtemperature with 100 μL/well of 1 μg/mL human α_(v)β₅ (Chemicon CC1025)in TS buffer. All subsequent steps were preformed at room temperature.Plates were blocked for 2 hr at 30□C with 150 μL/well of TSB buffer, andwashed 3 times with 200 μL/well of PBST buffer. Controls or testcompound (0.0001-20 μM) were mixed with 1 μg/mL of human vitronectin(Chemicon CC080) that had been biotinylated in-house withsulfo-NHS-LC-LC-biotin (Pierce 21338, 20:1 molar ratio), and 100 μL/wellof these solutions (in TSB buffer) were incubated for 2 hr. The platewas then washed 5 times with PBST buffer, and 100 μL/well of 0.25 μg/mL.NeutraAvidin-horseradish peroxidase conjugate (Pierce 31001) in TSBbuffer was incubated at 30° C. for 1 hr. Following a 5-fold PBST bufferwash, the plate was developed and results were calculated as describedfor the fibrinogen-IIbIIIa assay.

EXAMPLE 58 Tablet Preparation

Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of thecompound of Example 1 (“active compound”) are prepared as illustratedbelow TABLET FOR DOSES CONTAINING FROM 25-100 MG OF THE ACTIVE COMPOUNDAmount-mg Active compound 25.0 50.0 100.00 Microcrystalline cellulose37.25 100.0 200.0 Modified food corn starch 37.25 4.25 8.5 Magnesiumstearate 0.50 0.75 1.5

All of the active compound, cellulose, and a portion of the corn starchare mixed and granulated to 10% corn starch paste. The resultinggranulation is sieved, dried and blended with the remainder of the cornstarch and the magnesium stearate. The resulting granulation is thencompressed into tablets containing 25.0, 50.0, and 100.0 mg,respectively, of active ingredient per tablet.

EXAMPLE 59 Intravenous Solution Preparation

An intravenous dosage form of the compound of Example 1 (“activecompound”) is prepared as follows: Active compound 0.5-10.0 mg Sodiumcitrate 5-50 mg Citric acid 1-15 mg Sodium chloride 1-8 mg Water forinjection (USP) q.s. to 1 ml

Utilizing the above quantities, the active compound is dissolved at roomtemperature in a previously prepared solution of sodium chloride, citricacid, and sodium citrate in Water for Injection (USP, see page 1636 ofUnited States Pharmacopeia/National Formulary for 1995, published byUnited States Pharmacopeial Convention, Inc., Rockville, Md. (1994).

Having now fully described this invention, it will be understood tothose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations, and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

1-65. (canceled)
 66. A compound having the Formula IV:

wherein: R¹, R², R³, R⁴ and R⁵ independently represent hydrogen,halogen, alkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl; R⁶, R⁷, R⁸and R⁹ independently represent hydrogen, alkyl, hydroxyalkyl,aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, arylor aralkyl; or R⁶ and R⁷ are taken together to form —(CH₂)_(p)—, where pis 2-8, while R⁸ and R⁹ are defined as above; or R⁸ and R⁹ are takentogether to form —(CH₂)_(q)—, where q is 2-8, while R⁶ and R⁷ aredefined as above; or R⁶ and R⁸ are taken together to form —(CH₂)_(r)—,while r is zero (a bond), 1 or 2, while R⁷ and R⁹ are defined as above;X represents oxygen, sulfur, —CH₂—, —NH—, —(C═O)NH— or —NH(C═O)—; n isfrom 0 to 4; m is from 0 to 4; a is 0 or 1; D represents oxygen; v is 0or 1; R¹⁰, R¹¹, R¹² and R¹³ independently represent: hydrogen; hydroxy;alkyl; alkoxy; cycloalkyl; aryl, optionally substituted with one or moreof halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl,arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkylalkoxyaryl,monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl,dialkylaminoalkyl, alkanoyl; monoalkylamino; dialkylamino; aminoalkyl;monoalkylaminoalkyl; dialkylaminoalkyl; alkanoyl; heteroaryl having 5-14ring members, optionally substituted with one or more of halogen,hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy,aryloxy, alkylsulfonyl, alkylsulfinyl, alkylalkoxyaryl, monoalkylamino,dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,alkanoyl; or

wherein R¹⁷ and R¹⁸ together form —CH₂CH₂—O—, —O—CH₂CH₂—, —O—CH₂—O— or—O—CH₂CH₂—O—; or R¹⁰ and R¹² are taken together to form —(CH₂)_(n)—,wherein s is 0 (a bond) or 1 to 4, while R¹¹ and R¹³ are as defined asabove; or R¹⁰ and R¹² are taken together to form a double bond when i is0 and k is 1, while R¹¹ and R¹³ are as defined above; or R¹⁰ and R¹¹ aretaken together to form —(CH₂)_(t)—, wherein t is 2 to 8, while R¹² andR¹³ are as defined as above, or R¹² and R¹³ are taken together to form—(CH₂)_(n)— wherein u is 2 to 8, while R¹⁰ and R¹¹ are as defined asabove; i is from 0 to 4; j is from 0 to 4; k is 0 or 1; R¹⁴ is hydrogenor a functionality that acts as a prodrug (i.e., converts to the activespecies by an endogenous biological process such as an esterase, lipase,or other hydrolase), such as alkyl, aryl, aralkyl, dialkylaminoalkyl,1-morpholinoalkyl, 1-piperidinylalkyl, pyridinylalkyl,alkoxy(alkoxy)alkoxyalkyl, or (alkoxycarbonyl)oxyethyl; W is:

wherein: R¹⁵ is hydrogen, halogen, alkyl, aryl or arylalkyl; and R¹⁶ ishydrogen, alkyl, haloalkyl or halogen.
 67. The compound of claim 66,wherein R¹⁴ is a prodrug, selected from the group consisting of: alkyl,aryl, aralkyl, dialkylaminoalkyl, 1-morpholinoalkyl, 1-piperidinylalkyl,pyridinylalkyl, alkoxy(alkoxy)alkoxyalkyl, or (alkoxycarbonyl)oxyethyl.68. The compound of claim 66, wherein: R¹, R², R³, R⁴ and R⁵independently represent hydrogen, halogen, (C₁₋₈)alkyl, (C₆₋₁₀)aryl,(C₆₋₁₀)ar(C₁₋₈)alkyl, 5-14 member heteroaryl, or 5-14 memberheteroaryl(C₁₋₈)alkyl; R⁶, R⁷, R⁸ and R⁹ independently representhydrogen, (C₁₋₈)alkyl, hydroxy(C₁₋₈)alkyl, amino(C₁₋₈)alkyl,mono(C₁₋₈)alkylamino(C₁₋₈)alkyl, di(C₁₋₈)alkylamino(C₁₋₈)alkyl,carboxy(C₁₋₈)alkyl, (C₆₋₁₀)aryl or (C₆₋₁₀)ar(C₁₋₈)alkyl; or R⁶ and R⁷are taken together to form —(CH₂)_(p)—, where p is 2-8, while R⁸ and R⁹are defined as above; or R⁸ and R⁹ are taken together to form—(CH₂)_(q)—, where q is 2-8, while R⁶ and R⁷ are defined as above; or R⁶and R³ are taken together to form —(CH₂)_(r)—, while r is zero (a bond),1 or 2, while R⁷ and R⁹ are defined as above; X represents oxygen,sulfur, —CH₂—, —NH—, —(C═O)NH— or —NH(C═O)—; n is from 0 to 4; m is from0 to 4; a is from 0 or 1; D represents oxygen; v is from 0 or 1; R¹⁰,R¹¹, R¹² and R¹³ independently represent: hydrogen; hydroxy;(C₁₋₈)alkyl; (C₁₋₈)alkoxy; (C₃₋₈)cycloalkyl; (C₆₋₁₀)aryl, optionallysubstituted with one or more of halogen, hydroxy, cyano, (C₁₋₈)alkyl,(C₆₋₁₀)aryl, (C₁₋₈)alkoxy, halo(C₁₋₈)alkyl, (C₆₋₁₀)aryl(C₁₋₈)alkyl,(C₆₋₁₀)aryl(C₁₋₈)alkoxy, (C₆₋₁₀)aryloxy, (C₁₋₈)alkylsulfonyl,(C₁₋₈)alkylsulfinyl, (C₁₋₈)alkoxy(C₆₋₁₀)aryl(C₁₋₈)alkyl,mono(C₁₋₈)alkylamino, di(C₁₋₈)alkylamino, amino(C₁₋₈)alkyl,mono(C₁₋₈)alkylamino(C₁₋₈)alkyl, di(C₁₋₈)alkylamino(C₁₋₈)alkyl,(C₁₋₈)alkanoyl; mono(C₁₋₈)alkylamino; di(C₁₋₈)alkylamino;amino(C₁₋₈)alkyl; mono(C₁₋₈)alkylamino(C₁₋₈)alkyl;di(C₁₋₈)alkylamino(C₁₋₈)alkyl; (C₁₋₈)alkanoyl; heteroaryl having 5-14ring members, optionally substituted with one or more of halogen,hydroxy, cyano, (C₁₋₈)alkyl, (C₆₋₁₀)aryl, (C₁₋₈)alkoxy, halo(C₁₋₈)alkyl,(C₆₋₁₀)aryl(C₁₋₈)alkyl, (C₆₋₁₀)aryl(C₁₋₈)alkoxy, (C₆₋₁₀)aryloxy,(C₁₋₈)alkylsulfonyl, (C₁₋₈)alkylsulfinyl,(C₁₋₈)alkoxy(C₆₋₁₀)aryl(C₁₋₈)alkyl, mono(C₁₋₈)alkylamino,di(C₁₋₈)alkylamino, amino(C₁₋₈)alkyl, mono(C₁₋₈)alkylamino(C₁₋₈)alkyl,di(C₁₋₈)alkylamino(C₁₋₈)alkyl, (C₁₋₈)alkanoyl; or

wherein R¹⁷ and R¹⁸ together form —CH₂CH₂—O—, —O—CH₂CH₂—, —O—CH₂—O— or—O—CH₂CH₂—O—; or R¹⁰ and R¹² are taken together to form —(CH₂)_(n)—,wherein s is 0 (a bond) or 1 to 4, while R¹¹ and R¹³ are as defined asabove; or R¹⁰ and R¹² are taken together to form a double bond when i is0 and k is 1, while R¹¹ and R¹³ are as defined above; or R¹⁰ and R¹¹ aretaken together to form —(CH₂)_(t)—, wherein t is 2 to 8, while R¹² andR¹³ are as defined as above, or R¹² and R¹³ are taken together to form—(CH₂)_(n)— wherein u is 2 to 8, while R¹⁰ and R¹¹ are as defined asabove; or i is from 0 to 4; j is from 0 to 4; and k is 0 or 1; and R¹⁴is hydrogen or a functionality that acts as a prodrug.
 69. The compoundof claim 66, wherein R¹ and R² independently represent hydrogen,halogen, (C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)ar(C₁₋₆)alkyl, 5-14 memberheteroaryl, or 5-14 member heteroaryl(C₁₋₈)alkyl.
 70. The compound ofclaim 69, wherein R¹ and R² independently represent hydrogen, methyl,ethyl, propyl, butyl, phenyl, benzyl or phenylethyl.
 71. The compound ofclaim 70, wherein R¹ and R² independently represent hydrogen, methyl,ethyl or propyl.
 72. The compound of claim 66, wherein R³, R⁴ and R⁵independently represent hydrogen, (C₁₋₆)alkyl, (C₆₋₁₀)aryl, or(C₆₋₁₀)ar(C₁₋₆)alkyl.
 73. The compound of claim 72, wherein R³, R⁴ andR⁵ are hydrogen or (C₁₋₄)alkyl.
 74. The compound of claim 66, whereinR⁶, R⁷, R⁸ and R⁹ independently represent hydrogen, halogen or(C₁₋₆)alkyl.
 75. The compound of claim 66, wherein X is oxygen, —CH₂— or—(C═O)NH—.
 76. The compound of claim 75, wherein X is oxygen or —CH₂—.77. The compound of claim 66, wherein: X is —(C═O)NH—; n, m, a and v areeach 0; and R⁶, R⁷, R¹² and R¹³ are hydrogen.
 78. The compound of claim66, wherein: X is oxygen; n and m are each 0; a and v are each 1; D isoxygen; R⁶, R⁷, R⁸ and R⁹ are hydrogen.
 79. The compound of claim 66,wherein: X is oxygen; n, m and v are each 0; a is 1; and R⁶, R⁷, R¹² andR¹³ are hydrogen.
 80. The compound of claim 66, wherein: X is —CH₂—; n,m and v are each 0; a is 1; and R⁶, R⁷, R¹² and R¹³ are hydrogen. 81.The compound of claim 66, wherein v is
 0. 82. The compound of claim 66,wherein: R¹ is hydrogen or —CH₃; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ arehydrogen; X is oxygen or —CH₂—; n is 0 or 1; m is 0 or 1; R¹⁰, R¹¹, R¹²and R¹³ independently represent hydrogen, (C₁-C₆)alkyl or(C₆₋₁₀)ar(C₁₋₆)alkyl; or one of the combination R¹⁰ and R¹¹, R¹² and R¹³or R¹⁰ and R¹² are taken together to form —(CH₂)_(n)—, wherein s is 1while the remaining of R¹⁰—R¹³ are defined above; i is 0 or 1; j is 0 or1; k is 0 or 1; R¹⁴ is hydrogen or alkyl; W is:

wherein: R¹⁵ is hydrogen, halogen, (C₁₋₈)alkyl, (C₆₋₁₀)aryl or(C₆₋₁₀)aryl(C₁₋₈)alkyl; and R¹⁶ is hydrogen, (C₁₋₈)alkyl,halo(C₁₋₈)alkyl or halogen.
 83. The compound of claim 66, which is oneof: 3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;3-{5-[3-(2-pyridylamino)propoxy]indolyl}acetic acid;3-{2-methyl-5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;2-(trans-2-{5-[3-(2-pyridylamino)propoxy]indolyl}cyclopropyl)aceticacid; 3-(5-{2-[6-(methylamino)-2-pyridyl]ethoxy}indolyl)propanoic acid;2-benzyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;2-methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid;2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)pentanoic acid;2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)octanoic acid;3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-phenyl-propionicacid;3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-quinolin-3-yl-propionicacid;3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-3-pyridin-3-yl-propionicacid; 3-{5-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoicacid; or a pharmaceutically acceptable salt, hydrate, solvate or prodrugthereof.
 84. A pharmaceutical composition comprising a compound of claim66 and a pharmaceutically acceptable carrier or diluent.
 85. Thecompound according to claim 66, wherein R¹² and R¹³ are independentlyselected from: